Diseases affecting the craniofacial skeleton are normally associated with disturbances in the regulation of cellular differentiation, the development of bone structures, and changes in bone density and ossification. Thus, the objective of this integrative review is to evaluate the published scientific literature from the last 8 years concerning the impact of genetics on some craniofacial dysplasias. Our aim covers the identification of oral cavity alterations to those dysplasias, through the most common orofacial manifestations. Three dysplasias were selected to be part of this integrative review: cleidocranial dysplasia, ectodermal dysplasia and Apert syndrome. For this purpose, a bibliographic search was performed in the PubMed, ScienceDirect, Web of Science and Google Scholar databases with several keywords combined with each other. The research question of this review was as follows: "What is the impact of genetic factors on the development of craniofacial dysplasias and associated oral malformations?". After selecting the articles through the application of inclusion and exclusion criteria, 11 articles were selected for this review. Genetics plays a crucial role in craniofacial dysplasias and subsequent oral malformations. The main conclusion was that mutations in different genes can lead to identical phenotypes, while mutations in the same gene can present slight phenotypic differences depending on where they occur. In the future, it would be important to conduct studies with larger samples and control groups that include genetic testing to allow for a more comprehensive study on the impact of genetics on craniofacial dysplasias.

Congenital upper limb differences occur in approximately 20-30 per 10,000 live births. These differences frequently prompt reconstructive surgery and may present in isolation or as markers of systemic syndromes. Embryologically, limb development depends on coordinated signaling along the proximal-distal (apical ectodermal ridge/fibroblast growth factor [FGF]), radial-ulnar (zone of polarizing activity/sonic hedgehog), and dorsal-ventral (wingless-related integration site 7) axes, whose disruptions lead to specific phenotypic patterns. Among upper limb differences, those with a well-established genetic basis can be subcategorized as radial longitudinal deficiency, polydactyly, syndactyly, brachydactyly, ectrodactyly, and macrodactyly. Each phenotype exhibits distinctive radiographic features and associated clinical presentations, which guide syndrome-specific diagnosis. Notable genetic associations include TBX5 (Holt-Oram), FANCA (Fanconi anemia), GLI3 (Greig cephalopolysyndactyly), FGFR2 (Apert), and TP63 (ectrodactyly-ectodermal dysplasia clefting), as well as somatic mosaic mutations (eg, PIK3CA, AKT1, and RASA1) linked to overgrowth syndromes (eg, congenital lipomatous overgrowth, vascular differences, epidermal nevi, and spinal/skeletal differences; Proteus; and Parkes-Weber). Recognition of these patterns relies on imaging and targeted genetic testing. Advances in genomic sequencing have clarified the etiologies of previously classified associations, revealing monogenic or mosaic origins. Early and accurate syndromic identification enables coordinated care, informs management planning, and facilitates multidisciplinary collaboration to optimize functional and psychosocial outcomes.

Split hand-foot malformation (SHFM) is a congenital limb malformation affecting primarily the central rays of the hands and/or feet, with variable expressivity, incomplete penetrance and syndromic forms. It is genetically heterogeneous, including point mutations and structural variants in different loci. Five individuals with SHFM were clinically evaluated in a Tertiary Center in Brazil: four of them presented additional, nonskeletal findings, including one individual with split foot, hand syndactyly, and ectodermal findings. Structural variants and point mutations in genes associated with SHFM were identified in all individuals. Our results highlight genetic heterogeneity observed in this group of skeletal disorders, alongside incomplete penetrance, a challenging task imposed on genetic counseling. Of note, an individual harboring a recurrent heterozygous variant in MAP3K20 presented a phenotype reminiscent of TP63-related disorders, contrary to the one recently reported in the literature with prominent facial dysmorphisms, expanding the phenotypic spectrum of this newly recognized syndromic form of SHFM.

This study aims to investigate the phenotypes, mutation types, and loci associated with TP63-related syndrome by focusing on an affected proband. Employing a proband collection strategy, we identified a family presenting with TP63-related syndrome and performed thorough clinical evaluations on the proband and family members. We subsequently documented the phenotype, mutation type, and locus of the TP63 gene, followed by Sanger DNA sequencing analysis. We identified a family affected by TP63-related syndrome. The proband, a young adult male, demonstrated congenital anodontia, hypohidrosis, sparse hair, and additional features characteristic of ectodermal dysplasia. Further clinical manifestations included left ear hearing impairment, cleft lip/palate, hypospadias, and syndactyly. Sequencing analysis revealed a missense nucleotide variant (c.184G>C, p.Val62Leu) in exon 2 of the TP63 gene. This variant was absent from established SNP databases and was not detected in other family members or unrelated healthy individuals. The family exhibits significant symptoms consistent with TP63 syndrome. The identified missense mutation is preliminarily considered to be pathogenic.

Heterozygous variants in MAP3K20 have been implicated in a recently identified syndromic form of ectodermal dysplasia, distinguished by a unique combination of ectrodactyly, craniosynostosis, bilateral sensorineural hearing loss, and skeletal anomalies such as transverse limb defect, and brachydactyly. We present an 11-year-old male with ectrodactyly, ectodermal dysplasia, bilateral sensorineural hearing loss, and cutaneous syndactyly in both hands. A de novo heterozygous variant, c.837_839del p.(Asn279del), in MAP3K20 was identified in his whole exome sequencing. The results of this study emphasize the critical role of MAP3K20 as a key gene in conditions involving ectrodactyly, craniosynostosis, bilateral sensorineural hearing loss, ectodermal features, transverse limb defect, and brachydactyly. We highlight the importance of prioritizing the recurrent p.(Asn279del) variant in genetic testing for affected individuals. Furthermore, we propose an acronym for this dominant disorder caused by the MAP3K20 gene variants: DECES (Dominant/Deafness, Ectodermal Dysplasia, Craniosynostosis, Ectrodactyly, Skeletal anomalies).