Chordomas are tumors thought to originate from notochordal remnants that occur in midline structures from the cloves of the skull base to the sacrum. In adults, the most common location is the sacrum, followed by the clivus and then mobile spine, while in children a clival origin is most common. Most chordomas are slow growing. Clinical presentation of chordomas tend to occur late, with local invasion and large size often complicating surgical intervention. Radiation therapy with protons has been proven to be an effective adjuvant therapy. Unfortunately, few adjuvant systemic treatments have demonstrated significant effectiveness, and chordomas tend to recur despite intensive multimodal care. However, insight into the molecular underpinnings of chordomas may guide novel therapeutic approaches including selection for immune and molecular therapies, individualized prognostication of outcomes, and real-time noninvasive assessment of disease burden and evolution. At the genomic level, elevated levels of brachyury stemming from duplications and mutations resulting in altered transcriptional regulation may introduce druggable targets for new surgical adjuncts. Transcriptome and epigenome profiling have revealed promoter- and enhancer-dependent mechanisms of protein regulation, which may influence therapeutic response and long-term disease history. Continued scientific and clinical advancements may offer further opportunities for treatment of chordomas. Single-cell transcriptome profiling has further provided insight into the heterogeneous molecular pathways contributing to chordoma propagation. New technologies such as spatial transcriptomics and emerging biochemical analytes such as cell-free DNA have further augmented the surgeon-clinician\'s armamentarium by facilitating detailed characterization of intra- and intertumoral biology while also demonstrating promise for point-of-care tumor quantitation and assessment. Recent and ongoing clinical trials highlight accelerating interest to translate laboratory breakthroughs in chordoma biology and immunology into clinical care. In this review, the authors dissect the landmark studies exploring the molecular pathogenesis of chordoma. Incorporating this into an outline of ongoing clinical trials and discussion of emerging technologies, the authors aimed to summarize recent advancements in understanding chordoma pathogenesis and how neurosurgical care of chordomas may be augmented by improvements in adjunctive treatments.

OBJECTIVE: To explore the clinical characteristics and genetic basis for a child with global developmental delay and autism.
METHODS: A child who had presented at West China Second University Hospital of Sichuan University on April 13, 2021 was selected as the study subject. Clinical manifestations, laboratory examination and result of genetic testing were analyzed.
RESULTS: The main symptoms of the child had included cognitive, language and motor delay, autism and epilepsy. Electroencephalogram revealed multiple focal discharges in both waking and sleeping stages, with the remarkable one seen at the sleeping stage. Cranial MRI showed pachygyria and local cortical thickening, Whole exome sequencing (WES) revealed that the child has harbored a heterozygous c.1589_1595dup (p.Gly533Leufs*143) frameshifting variant in the TBR1 gene (OMIM 604616). Based on the guidelines from the American College of Medical Genetics and Genomics, the variant was predicted to be likely pathogenic (PS2+PVS1_Supporting+PM2_Supporting). After treated with levetiracetam and rehabilitation training, the child did not have seizure in the past 5 months, and his motor development has also significantly improved.
CONCLUSIONS: The c.1589_1595dup variant of the TBR1 gene probably underlay the disease in this patient.

TBX4 gene, located on human chromosome 17q23.2, encodes for T-Box Transcription Factor 4, a transcription factor that belongs to the T-box gene family and it is involved in the regulation of some embryonic developmental processes, with a significant impact on respiratory and skeletal illnesses. Herein, we present the case of a female neonate with persistent pulmonary hypertension (PH) who underwent extracorporeal membrane oxygenation (ECMO) on the first day of life and then resulted to have a novel variant of the TBX4 gene identified by Next-Generation Sequencing. We review the available literature about the association between PH with neonatal onset or emerging during the first months of life and mutations of the TBX4 gene, and compare our case to previously reported cases. Of 24 cases described from 2010 to 2023 sixteen (66.7%) presented with PH soon after birth. Skeletal abnormalities have been described in 5 cases (20%). Eleven cases (46%) were due to de novo mutations. Three patients (12%) required ECMO. Identification of this variant in affected individuals has implications for perinatal and postnatal management and genetic counselling. We suggest including TBX4 in genetic studies of neonates with pulmonary hypertension, even in the absence of skeletal abnormalities.

T-Box Transcription Factor 5 (TBX5) variants are associated with Holt-Oram syndrome. Holt-Oram syndrome display phenotypic variability, regarding upper limb defects, congenital heart defects, and arrhythmias. To investigate the genotype-phenotype relationship between TBX5 variants and cardiac disease, we performed a systematic review of the literature. Through the systematic review we identified 108 variants in TBX5 associated with a cardiac phenotype in 277 patients. Arrhythmias were more frequent in patients with a missense variant (48% vs 30%, p = 0.009) and upper limb abnormalities were more frequent in patients with protein-truncating variants (85% vs 64%, p = 0.0008). We found clustering of missense variants in the T-box domain. Furthermore, we present a family with atrial septal defects. By whole exome sequencing, we identified a novel missense variant p.Phe232Leu in TBX5. The cardiac phenotype included atrial septal defect, arrhythmias, heart failure, and dilated cardiomyopathy. Clinical examination revealed subtle upper limb abnormalities. Thus, the family corresponds to the diagnostic criteria of Holt-Oram syndrome. We provide an overview of cardiac phenotypes associated with TBX5 variants and show an increased risk of arrhythmias associated to missense variants compared to protein-truncating variants. We report a novel missense variant in TBX5 in a family with an atypical Holt-Oram syndrome phenotype.

Ulnar-Mammary syndrome (UMS) is a rare monogenic disorder caused by mutations of the TBX3 gene. This paper reported a family of UMS. The proband, a 15-year old man, was presented with mammary gland dysplasia, ulnar limb defect, short stature, and delayed growth. Whole exome sequencing revealed a 1294_1301dup mutation in exon 6 of the TBX3 gene. Sanger sequencing was used to verify other members of the family, which suggested his mother also carried the same mutation, but merely resulting in the dysplasia of her left little finger. Notably, unilateral finger involvement without any systemic organ involvement was unusual in UMS patients. The proband then was treated with recombinant human growth hormone (rhGH) and human chorionic gonadotropin (hCG). After a year and a half, his height and secondary sexual characteristics were significantly improved. The clinical manifestations of the disease are highly heterogeneous, which is easy to be misdiagnosed and missed. When the diagnosis is unclear, genetic testing is helpful for auxiliary diagnosis.
Ulnar-Mammary综合征(Ulnar-Mammary syndrome，UMS)是由TBX3基因突变所致的一种罕见单基因遗传病。本文报告1个UMS家系，先证者为15岁男性患者，表现为乳腺发育不良、尺侧肢体缺陷、身材矮小和发育迟缓。全外显子测序发现其TBX3基因的第6外显子存在1294_1301dup变异。用Sanger测序验证家系中其他成员，结果提示患者母亲也携带同样的突变，但仅表现为左侧小指发育异常。仅单侧手指受累而无任何系统器官受累的UMS患者鲜有报道。予患者重组人生长激素(recombinant human growth hormone，rhGH)和人绒毛膜促性腺激素(human chorionic gonadotropin，hCG)治疗1年半，身高及第二性征均得到明显改善。该疾病的临床表现异质性强，容易误诊漏诊，当诊断不明时，基因检测有助于辅助诊断。.

BACKGROUND: Although histopathology remains in the first line of the diagnosis of pituitary pathology, immunohistochemistry and molecular biology are currently in charge of providing a more accurate characterisation of tumours in this field.
METHODS: A systematic review of the literature was performed, using the PubMed and SCOPUS databases, with terms that included transcription factors involved in the development of pituitary tumours: T-PIT, PIT-1, and SF-1.
RESULTS: The results showed different perspectives, but the evidence is in favour of a multifold immunohistochemical analysis that must include pituitary transcription factors for a highly accurate diagnosis, prognosis, and guidance of (multimodal) therapy.
CONCLUSIONS: By using transcription factors, the understanding of the structure and function of the recently defined pituitary neuroendocrine tumours has made significant progress. This approach brings the (sub)classification of pituitary tumours, using cell types and cell lineages, with clinical and molecular implications and therapeutic results.

Chordomas are uncommon, bone, axial, or (rarely) extra-axial tumors that are malignant and frequently recur but less commonly metastasize. They usually affect adults, with a very small proportion being pediatric tumors. For children, such tumors present a different biology, since they are more common as scull rather than sacral tumors, with aggressive histological features, including a loss of SMARCB1/INI1 and a dismal prognosis. Histologically, chordomas, believed to derive from notochordal tissue, characteristically show physaliphorous cells in a myxoid or chondroid matrix. Dedifferentiated and poorly differentiated forms can be observed. Moreover, a grading scale for chordomas has been proposed. Cytokeratin, EMA, S100, and brachyury are expressed by most chordomas. These are chemo-resistant tumors, for which surgical resection and/or radiotherapy are the treatments of choice. In this review, the histological, immunohistochemical, molecular, and clinical data of chordomas are discussed.

T-box transcription factor gene (TBX) interferes with the origin and development of organs, and TBX5 is expressed highest in normal cardiac and pulmonary tissues. Lack of TBX5 may lead to thoracic malformation and abnormal diaphragmatic development, in which ectopic expression and overexpression may induce the apoptosis of cell and inhibit the development of cell. Previous studies demonstrated the potential role of TBX5 in the development and progression of esophageal adenocarcinoma, gastric cancer, colon cancer and breast cancer. We reviewed the association between the expression of TBX2 subfamily and the prognosis, and explore the research progress of TBX5 in regulating the development and progression of lung cancer. Even though the relationshihp the development of lung cancer and TBX5 are not clear, TBX5 could significantly inhibit in vivo tumor growth, and the level of TBX5 was negatively correlated with lung cancer progression. Therefore, the gene expression levels and methylation extent of TBX could be a potential biomarker to reveal the proliferation and metastasis of lung cancer, as well as a therapeutic target for lung cancer.
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【中文题目：TBX5基因在肺癌中的研究进展】 【中文摘要：T-box转录因子（T-box transcription factor gene, TBX）基因涉及器官的发生，TBX5在人的正常心脏和肺组织中表达水平最高。TBX5的缺乏可能导致胸廓发育畸形和膈肌发育异常，其异位表达和过表达会诱导细胞凋亡和抑制细胞生长。既往研究发现了TBX5在食管腺癌、胃癌、结肠癌和乳腺癌的发生和发展中的潜在作用。我们对TBX2亚家族的基因表达和预后之间的关系进行了综述，同时探究TBX5在调控肺癌发生发展机制中的研究进展。虽然TBX5和肺癌发生之间的关系尚不明确，不过TBX5可以显著抑制人体内肿瘤生长，其表达水平和肺癌的进展呈现负相关。由此，TBX5的基因表达水平和甲基化程度是潜在的表证肺癌增殖和转移的生物标志物，具有作为肺癌治疗靶点的潜力。
】 【中文关键词：T-box转录因子；肺肿瘤；基因表达；DNA甲基化；疾病进展】.

BACKGROUND: Isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) is a rare cause of adrenal insufficiency and T-box pituitary restricted transcription factor (TBX19) mutations are responsible for two-thirds of the neonatal onset form of the disease. IAD presents with hypoglycemia and prolonged jaundice in the neonatal period. TBX19 is important for both pro-opiomelanocortin (POMC) gene transcription and differentiation of POMC-expressing cells. We describe 2 patients, 1 with a reported and 1 with a novel TBX19 mutation, and present information about the long-term follow-up of these patients.
METHODS: Both patients had critical illnesses, recurrent hypoglycemia, convulsions, and neonatal hyperbilirubinemia. They also had low cortisol and ACTH levels, while other pituitary hormones were within the normal range. Pituitary imaging was normal. After hydrocortisone treatment, there was resolution of the hypoglycemia and the convulsions were controlled. Genetic studies of the patients revealed both had inherited a homozygous mutation of the TBX19 gene. The first patient had an alteration of NM_005149.3:c.856C>T (p.R286*) and the second patient had a novel NM_005149.3:c.584C>T (p.T195I) mutation, analyzed by next-generation sequencing. The noteworthy findings of the patients at follow-up were: short stature, microcephaly, and decreased pubic hair in the first, and dysmorphic features, Chiari type 1 malformation, tall stature, and low bone mineral density (BMD) in the second.
CONCLUSIONS: Congenital IAD can be life-threatening if it is not recognized and treated early. TBX19 mutations should be considered in the differential diagnosis of IAD. Further cases or functional analyses are needed for genotype-phenotype correlations. Low BMD, dysmorphic features, Chiari type 1 malformation, and sparse pubic hair are some of the important features in these patients.

TBR1, a T-box transcription factor expressed in the cerebral cortex, regulates the expression of several candidate genes for autism spectrum disorders (ASD). Although TBR1 has been reported as a high-confidence risk gene for ASD and intellectual disability (ID) in functional and clinical reports since 2011, TBR1 has only recently been recorded as a human disease gene in the OMIM database. Currently, the neurodevelopmental disorders and structural brain anomalies associated with TBR1 variants are not well characterized. Through international data sharing, we collected data from 25 unreported individuals and compared them with data from the literature. We evaluated structural brain anomalies in seven individuals by analysis of MRI images, and compared these with anomalies observed in TBR1 mutant mice. The phenotype included ID in all individuals, associated to autistic traits in 76% of them. No recognizable facial phenotype could be identified. MRI analysis revealed a reduction of the anterior commissure and suggested new features including dysplastic hippocampus and subtle neocortical dysgenesis. This report supports the role of TBR1 in ID associated with autistic traits and suggests new structural brain malformations in humans. We hope this work will help geneticists to interpret TBR1 variants and diagnose ASD probands.