AXIN2-related oligodontia-colorectal cancer syndrome with cleft palate as a possible new feature

Background: Pathogenic variants in AXIN2 have been associated with tooth agenesis, colon polyps, and colon cancer. Given the rare nature of this phenotype, we set out to collect additional genotypic and phenotypic information. Methods: Data were collected via a structured questionnaire. Sequencing was performed in these patients mostly due to diagnostic purpose. A little more than half of the AXIN2 variant carriers were identified by NGS; other six were family members. Results: Here, we report 13 individuals with a heterozygous AXIN2 pathogenic/likely pathogenic variant who have a variable expression of oligodontia-colorectal cancer syndrome (OMIM 608615) or oligodontia-cancer predisposition syndrome (ORPHA 300576). Three individuals from one family also had cleft palate, which might represent a new clinical feature of AXIN2 phenotype, also given the fact that AXIN2 polymorphisms have been found in association with oral clefting in population studies. AXIN2 has already been added to multigene cancer panel tests; further research should be conducted to determine whether it should be added to cleft lip/palate multigene panels. Conclusion: More clarity about oligodontia-colorectal cancer syndrome, about the variable expression, and associated cancer risks is needed to improve clinical management and to establish guidelines for surveillance. We collected information about the surveillance that was advised, which might support clinical management of these patients.</p

Salivary gland branching morphogenesis: a quantitative systems analysis of the Eda/Edar/NFκB paradigm

<p>Abstract</p> <p>Background</p> <p>Ectodysplasin-A appears to be a critical component of branching morphogenesis. Mutations in mouse <it>Eda </it>or human <it>EDA </it>are associated with absent or hypoplastic sweat glands, sebaceous glands, lacrimal glands, salivary glands (SMGs), mammary glands and/or nipples, and mucous glands of the bronchial, esophageal and colonic mucosa. In this study, we utilized <it>Eda</it>^{<it>Ta </it>}(Tabby) mutant mice to investigate how a marked reduction in functional Eda propagates with time through a defined genetic subcircuit and to test the proposition that canonical NFκB signaling is sufficient to account for the differential expression of developmentally regulated genes in the context of <it>Eda </it>polymorphism.</p> <p>Results</p> <p>The quantitative systems analyses do not support the stated hypothesis. For most NFκB-regulated genes, the observed time course of gene expression is nearly unchanged in Tabby (<it>Eda</it>^<it>Ta</it>) as compared to wildtype mice, as is NFκB itself. Importantly, a subset of genes is dramatically differentially expressed in Tabby (<it>Edar</it>, <it>Fgf8</it>, <it>Shh</it>, <it>Egf</it>, <it>Tgfa</it>, <it>Egfr</it>), strongly suggesting the existence of an alternative Eda-mediated transcriptional pathway pivotal for SMG ontogeny. Experimental and <it>in silico </it>investigations have identified C/EBPα as a promising candidate.</p> <p>Conclusion</p> <p>In Tabby SMGs, upregulation of the Egf/Tgfα/Egfr pathway appears to mitigate the potentially severe abnormal phenotype predicted by the downregulation of Fgf8 and Shh. Others have suggested that the buffering of the phenotypic outcome that is coincident with variant Eda signaling could be a common mechanism that permits viable and diverse phenotypes, normal and abnormal. Our results support this proposition. Further, if branching epithelia use variations of a canonical developmental program, our results are likely applicable to understanding the phenotypes of other branching organs affected by <it>Eda </it>(<it>EDA</it>) mutation.</p

Are Botulinum Toxin Injections Into the Major Salivary Glands a Good Treatment Option?

There are several treatment options available for drooling; botulinum toxin injections into the major salivary glands are one. There is no consensus as to how many and which glands should be injected. A research project on this topic was terminated because of adverse effects. Individual results and the adverse effects are described and discussed in this article. Six individuals with cerebral palsy were randomly allocated to 2 treatment groups, with five individuals receiving ultrasound-guided injections to parotid and submandibular glands and one receiving injections to the submandibular glands only. Reduction of observed drooling was registered in 3, while 4 patients reported subjective improvement (Visual Analog Scale). Two participants reported adverse effects, including dysphagia, dysarthria, and increased salivary viscosity. Injections with botulinum toxin can be a useful treatment option but there is a risk of adverse effects. Multidisciplinary evaluation and informed discussions with patients/caregivers are important factors in the decision-making process