DLX3 is a homeobox transcription factor essential for multiple organogenesis processes. Mutations in DLX3 cause trichodentoosseous syndrome (TDO), characterized by curly hair, sclerotic bone, enamel, and dentin defects as well as taurodontism. Phenotypic variability in TDO has been well documented, but its pathogenesis remains poorly understood. Here, we characterized three TDO families with distinct clinical features and identified a known DLX3 deletion (c.561_562del) and the first pathogenic splice-site variant (c.516+1_516+2insA). The proband with the splice-site mutation displayed a mesenchymal-dominant phenotype with severe dentin hypoplasia, enlarged pulp chambers, and hypertaurodontism but nearly normal enamel, whereas the mother and sister showed epithelial-dominant anomalies, including enamel hypoplasia and kinky hair. Minigene analysis demonstrated that c.516+1_516+2insA generated two aberrant transcripts encoding p.Val173Aspfs*28 and p.Arg120_Val173del. These mutant proteins localized mainly in the cytoplasm and showed markedly reduced transactivation activity. In cultured human dental pulp cells, DLX3 overexpression upregulated the odontoblastic markers DSPP, MMP20, and WNT10A. Chromatin immunoprecipitation and reporter assays further revealed that DLX3 directly activates WNT10A via a conserved enhancer (chr2:218,878,973_218,879,302) and three upstream binding sites. These findings expand the TDO mutational spectrum and suggest that differential mutant DLX3 expression may contribute to phenotypic variability, whereas disrupted regulation of WNT10A underlies dentin defects and taurodontism.

Tricho-dento-osseous syndrome (TDOS), a rare autosomal dominant condition caused by mutations in DLX3, is characterized by abnormalities in teeth, bone, and hair. This systematic review and meta-analysis summarized the most frequently reported dento-craniofacial features of TDOS. Searches were undertaken in five databases supplemented by manual scrutiny and a gray literature search. Observational and descriptive studies were included. Risk of bias was appraised using the Joanna Briggs Institute tools. Meta-analyses of continuous, binary, and proportion data were performed, with results reported as odds ratio (OR) and 95% confidence intervals (CI). Twenty-seven studies describing 297 individuals with TDOS were included. Most studies demonstrated a low risk of bias. Taurodontism (70.5%), enamel hypoplasia (34.5%), and dental infections (28.7%) were the most prevalent dental findings. Increased bone density/thickness (43.8%) was the primary skeletal manifestation, and sparse hair (27.2%) was the most common hair abnormality. Meta-analyses revealed high odds for taurodontism (OR = 42.71; 95% CI = 7.45-244.75) and consistent prevalence estimates for taurodontism (73%; 95% CI = 0.52-0.97) and enamel hypoplasia (71%; 95% CI = 0.52-0.97). Data confirm that TDOS predominantly affects dental, skeletal, and hair structures, highlighting the need for early diagnosis, multidisciplinary care, and tailored treatment approaches.

Osteogenesis Imperfecta (OI) is a heterogeneous skeletal dysplasia characterized by bone fragility, skeletal deformities, and short stature. Most commonly, it is caused by autosomal dominant variants in the type I collagen genes, COL1A1 or COL1A2. Type I collagen is the main protein of the extracellular matrix in the skeleton and changes in its structure or quantity may lead to OI. 85%-90% of OI cases occur due to sequence variants in type I collagen genes, while OI caused by structural abnormalities in type I collagen genes is less common. In most cases, haploinsufficiency of type I collagen is associated with a milder OI phenotype. Large genomic deletions often involve several genes within the same chromosomal region, leading to microdeletion syndromes with OI features. Here, we report eight Swedish patients from five unrelated families with OI due to structural variants in the COL1A1 and COL1A2 genes. One patient with OI type III had a complex rearrangement with a deletion and duplication event in COL1A2, leading to reduced COL1A2 expression. Three other patients from two different families with OI type I had whole gene deletions involving COL1A1. In one family, three affected individuals with OI type I had a small intragenic deletion of exons 11-12 in COL1A2. One patient had a 2.1 Mb de novo deletion encompassing COL1A1 and DLX3 genes and features of OI and tricho-dento-osseous syndrome. Overall, this study highlights the importance of investigating gene dosage abnormalities in patients with OI and further delineates clinical and genetic variability of OI caused by structural variants in type I collagen genes.

Skeletal Class III (SCIII) is among the most challenging craniofacial dysmorphologies to treat. There is, however, a knowledge gap regarding which syndromes share this clinical phenotype. The aims of this study were to: (i) identify the syndromes affected by the SCIII phenotype; (ii) clarify the involvement of maxillary and/or mandibular structures; (iii) explore shared genetic/molecular mechanisms. A two-step strategy was designed: [Step#1] OMIM, MHDD, HPO, GeneReviews and MedGen databases were explored; [Step#2]: Syndromic conditions indexed in [Step#1] were explored in Medline, Pubmed, Scopus, Cochrane Library, WOS and OpenGrey. Eligibility criteria were defined. Individual studies were assessed for risk of bias using the New Ottawa Scale. For quantitative analysis, a meta-analysis was conducted. This scoping review is a hypothesis-generating research. Twenty-two studies met the eligibility criteria. Eight syndromes affected by the SCIII were targeted: Apert syndrome, Crouzon syndrome, achondroplasia, X-linked hypohidrotic ectodermal dysplasia (XLED), tricho-dento-osseous syndrome, cleidocranial dysplasia, Klinefelter and Down syndromes. Despite heterogeneity between studies [p < 0.05], overall effects showed that midface components were affected in Apert and Down Syndromes, lower face in Klinefelter Syndrome and midface and lower face components in XLED. Our review provides new evidence on the craniofacial characteristics of genetically confirmed syndromes exhibiting the SCIII phenotype. Four major regulatory pathways might have a modulatory effect on this phenotype. IMPACT: What does this review add to the existing literature? To date, there is no literature exploring which particular syndromes exhibit mandibular prognathism as a common trait. Through this research, it was possibly to identify the particular syndromes that share the skeletal Class III phenotype (mandibular prognathism) as a common trait highlighting the common genetic and molecular pathways between different syndromes acknowledging their impact in craniofacial development.