Tricho-dento-osseous syndrome (TDO syndrome; OMIM #190320) is a rare autosomal dominant disorder characterized by abnormal development of the hair, teeth and bones. It was first discovered and reported by Lichtenstein et al. in 1972 in a six-generation Irish American family (Lichtenstein et al., 1972). The most common clinical manifestations are kinky, curly hair at birth (Price et al., 1998, Lee et al., 2008, Mayer et al., 2010, Nieminen et al., 2011, Li et al., 2015, Whitehouse et al., 2019, Liu et al., 2022), enamel hypoplasia, taurodontism, and increased thickness/density of bones (Price et al., 1998, Wright et al., 2008, Nieminen et al., 2011, Li et al., 2015, Jain et al., 2017, Liu et al., 2022). Other less reported clinical manifestations include brittle nails (Lee et al., 2008, Nieminen et al., 2011, Liu et al., 2022) and skin lesions (such as atopic dermatitis; Mayer et al., 2010).

In 1998, Price et al. confirmed that TDO syndrome was caused by a mutation in the DLX3 gene at 17q21 (Price et al., 1998). To date, 13 related DLX3 mutations that lead to TDO syndrome have been reported (Price et al., 1998, Dong et al., 2005, Lee et al., 2008, Wright et al., 2008, Mayer et al., 2010, Nieminen et al., 2011, Li et al., 2015, Jain et al., 2017, Whitehouse et al., 2019, Liu et al., 2022). The DLX3 gene encodes a transcription factor that plays an indispensable role in placental formation and embryonic development. Targeted deletion of the mouse DLX3 gene resulted in death between embryonic day 9.5 and day 10 (Morasso et al., 1999). In mice, the DLX3 gene is first expressed in neural crest cells and then specifically expressed in placenta, skin, bone, and epithelial mesenchymal-induced tissues and organs such as teeth and hair follicles (Beanan & Sargent, 2000). During the development of the mouse tooth germ, DLX3 expression is present through the initial stage of development, morphogenesis, and tissue formation stages (Lézot et al., 2008, Zhao et al., 2000). Similarly, the DLX3 gene also plays an important role in the development of human teeth, and the deficiency in protein expression is clearly related to the clinical characteristics of TDO. TDO patients carrying DLX3 mutations all exhibit clinical signs of enamel hypoplasia (Wright et al., 1997).

In the process of enamel development, the sequential expression and secretion of enamel matrix proteins (EMPs) are crucial and considered coregulated by cytokines, transcription factors, growth factors and signalling molecules (Miletich and Sharpe, 2003, Bei, 2009). An in vitro study showed that DLX3, as a transcription factor, could regulate the expression of EMP genes such as Amelx, Enam, Klk4, and Odam, thereby affecting enamel formation and mineralization (Zhang et al., 2015). Therefore, mutations in DLX3 may interfere with the normal development of enamel by regulating the expression of EMP genes, leading to abnormal morphology and structure.

In this study, we describe a Chinese family with clinical manifestations of TDO and identify a new frame-shift mutation in DLX3 in this family. We detect the thickness, microhardness, constituent elements, microstructure of enamel and hair microstructure of members of the family with the disease. Moreover, the impact of the newly discovered mutation on ameloblast differentiation is analysed in in vitro experiments, and possible molecular mechanisms are explored. This study further enriches the variation spectrum and the evidence for the molecular genetics of DLX3 mutations.