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In the development of a new diagnostic motor performance test to spare more children from painful muscle biopsy, seven functional items were used to measure muscle strength and muscle endurance in a prospective study on new patients. Over a 2-year period, 22 patients (12 males, 10 females; mean age 8y 1mo [SD 2y 6mo], range 4–11y) were recruited for the study. They had all been referred with suspected myopathy. The motor performance test was administered before muscle biopsy. Validity of the seven items was assessed using logistic regression analysis and receiver operating characteristic (ROC) analysis. Two items were withdrawn from the test because they were not suitable for children aged 4 to 5 years. The five remaining items were: Heels, Circuit, Stairs, Jump, and Gowers. A full logistic regression model including these five items was fitted to the total population of 90 patients suspected of having myopathy (from this study and our previous study) to make the best prediction of whether myopathy was present. The ROC area under the curve of the diagnostic prediction model was 0.92 (95% confidence interval [CI] 0.87–0.98) and 0.89 (95% CI 0.87–0.92) after bootstrap correction. This indicated the high diagnostic power that can be expected for future, similar patients. This non-invasive and child-friendly motor performance test can improve diagnostic procedure and, therefore, spare more children from unnecessary muscle biopsy. [ABSTRACT FROM AUTHOR]

To spare more children from painful muscle biopsy, a new non-invasive diagnostic motor performance test is undergoing development. Fifteen functional items were used to measure muscle strength and muscle endurance in 68 patients (47 males, 21 females; mean age 7y 8mo, SD 2y 2mo; range 4 to 11y), who had been referred to our specialist centre in the past 3 years on suspicion of myopathy. All the patients had undergone muscle biopsy. To correct the patients' outcomes for age, sex, and body size, regression prediction equations were obtained from a stratified random sample of 64 normally developing primary-school children aged 4 to 11 years (32 males, 32 females; mean age 8y 1mo, SD 2y 4mo). Feasibility was evaluated on the basis of five criteria. Validity was assessed using logistic regression analysis, receiver operating characteristic analysis, and sensitivity and specificity at a specifically chosen cut-off point. Reproducibility was evaluated by test–retest reliability in a stratified random sample of 40 patients who returned for re-measurements using the intraclass correlation coefficient. Seven items satisfied all five feasibility criteria, had high diagnostic power, and high test–retest reliability. The motor performance test can improve diagnostic procedure in children suspected of having myopathy. [ABSTRACT FROM AUTHOR]

The tympanic membrane (i.e. eardrum) sits at the interface between the middle and external ear. The tympanic membrane is composed of three layers: an outer ectoderm-derived layer, a middle neural crest-derived fibroblast layer with contribution from the mesoderm-derived vasculature, and an inner endoderm-derived mucosal layer. These layers form a thin sandwich that is often perforated following trauma, pressure changes or middle ear inflammation. During healing, cells need to bridge the perforation in the absence of an initial scaffold. Here, we assessed the contribution, timing and interaction of the different layers during membrane repair by using markers and reporter mice. We showed that the ectodermal layer is retracted after perforation, before proliferating away from the wound edge, with keratin 5 basal cells migrating over the hole to bridge the gap. The mesenchymal and mucosal layers then used this scaffold to complete the repair, followed by advancement of the vasculature. Finally, differentiation of the epithelium led to formation of a scab. Our results reveal the dynamics and interconnections between the embryonic germ layers during repair and highlight how defects might occur., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

A mesiodens is a supernumerary tooth located in the midline of the premaxilla. To investigate the genetic cause of mesiodens, clinical and radiographic examination were performed on 23 family members of a two-generation Hmong family. Whole exome sequencing (WES) or Sanger sequencing were performed in 22 family members and two unrelated Thai patients with mesiodens. WES in the Hmong family revealed a missense mutation (c.1807G>A;p.Glu603Lys) in PTPN23 in seven affected members and six unaffected members. The mode of inheritance was autosomal dominance with incomplete penetrance (53.84%). Two additional mutations in PTPN23 , c.2248C>G;p.Pro750Ala and c.3298C>T;p.Arg1100Cys were identified in two unrelated patients with mesiodens. PTPN23 is a regulator of endosomal trafficking functioning to move activated membrane receptors, such as EGFR, from the endosomal sorting complex towards the ESCRT-III complex for multivesicular body biogenesis, lysosomal degradation, and subsequent downregulation of receptor signaling. Immunohistochemical study and RNAscope on developing mouse embryos showed broad expression of PTPN23 in oral tissues, while immunofluorescence showed that EGFR was specifically concentrated in the midline epithelium. Importantly, PTPN23 mutant protein was shown to have reduced phosphatase activity. In conclusion, mesiodens were associated with genetic variants in PTPN23 , suggesting that mesiodens may form due to defects in endosomal trafficking, leading to disrupted midline signaling.

High incidence of chronic otitis media is associated with human craniofacial syndromes, suggesting that defects in the formation of the middle ear and associated structures can have a knock-on effect on the susceptibility to middle ear inflammation. Patients with branchio-oto-renal (BOR) syndrome have several defects in the ear leading to both sensorineural and conductive hearing loss, including otitis media. 40% of BOR syndrome cases are due to Eya1 haploinsufficiency, with mouse models affecting Eya1 , mimicking many of the defects found in patients. Here, we characterize the onset, consequences, and underlying causes of chronic otitis media in Eya1 heterozygous mice. Cavitation defects were evident in these mice from postnatal day (P)11 onwards, with mesenchyme around the promontory and attic regions of the middle ear space. This mesenchyme was still prominent in adult Eya1 heterozygous mice, while the wild-type littermates had fully aerated ears from P14 onwards. MicroCT analysis highlighted a significantly smaller bulla, confirming the link between bulla size defects and the ability of the mesenchyme to retract successfully. Otitis media was observed from P14, often presenting unilaterally, resulting in hyperplasia of the middle ear mucosa, expansion of secretory cells, defects in the motile cilia, and changes in basal epithelial cell markers. A high incidence of otitis media was identified in older mice but only associated with ears with retained mesenchyme. To understand the impact of the environment, the mouse line was rederived onto a super-clean environment. Cavitation defects were still evident at early stages, but these generally resolved over time, and importantly, no signs of otitis media were observed at 6 weeks. In conclusion, we show that a small bulla size is closely linked to defects in cavitation and the presence of retained mesenchyme. A delay in retraction of the mesenchyme predates the onset of otitis media, making the ears susceptible to its development. Early exposure to OM appears to exacerbate the cavitation defect, with mesenchyme evident in the middle ear throughout the animal's life. This highlights that permanent damage to the middle ear can arise as a consequence of the early onset of OM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fons, Milmoe, Dack, Joshi, Thompson and Tucker.)

Defects in ear canal development can cause severe hearing loss as sound waves fail to reach the middle ear. Here, we reveal new mechanisms that control human canal development and highlight for the first time the complex system of canal closure and reopening. These processes can be perturbed in mutant mice and in explant culture, mimicking the defects associated with canal atresia. The more superficial part of the canal forms from an open primary canal that closes and then reopens. In contrast, the deeper part of the canal forms from an extending solid meatal plate that opens later. Closure and fusion of the primary canal was linked to loss of periderm, with failure in periderm formation in Grhl3 mutant mice associated with premature closure of the canal. Conversely, inhibition of cell death in the periderm resulted in an arrest of closure. Once closed, re-opening of the canal occurred in a wave, triggered by terminal differentiation of the epithelium. Understanding these complex processes involved in canal development sheds light on the underlying causes of canal atresia., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

The pinna (or auricle) is part of the external ear, acting to capture and funnel sound toward the middle ear. The pinna is defective in a number of craniofacial syndromes, including Lacrimo-auriculo-dento-digital (LADD) syndrome, which is caused by mutations in FGF10 or its receptor FGFR2b . Here we study pinna defects in the Fgf10 knockout mouse. We show that Fgf10 is expressed in both the muscles and forming cartilage of the developing external ear, with loss of signaling leading to a failure in the normal extension of the pinna over the ear canal. Conditional knockout of Fgf10 in the neural crest fails to recapitulate this phenotype, suggesting that the defect is due to loss of Fgf10 from the muscles, or that this source of Fgf10 can compensate for loss in the forming cartilage. The defect in the Fgf10 null mouse is driven by a reduction in proliferation, rather than an increase in cell death, which can be partially phenocopied by inhibiting cell proliferation in explant culture. Overall, we highlight the mechanisms that could lead to the phenotype observed in LADD syndrome patients and potentially explain the formation of similar low-set and cup shaped ears observed in other syndromes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Zhang, Fons, Hajihosseini, Zhang and Tucker.)

Background: The egg tooth is a vital structure allowing hatchlings to escape from the egg. In squamates (snakes and lizards), the egg tooth is a real tooth that develops within the oral cavity at the top of the upper jaw. Most squamates have a single large midline egg tooth at hatching, but a few families, such as Gekkonidae, have two egg teeth. In snakes the egg tooth is significantly larger than the rest of the dentition and is one of the first teeth to develop., Results: We follow the development of the egg tooth in four snake species and show that the single egg tooth is formed by two tooth germs. These two tooth germs are united at the midline and grow together to produce a single tooth. In culture, this merging can be perturbed to give rise to separate smaller teeth, confirming the potential of the developing egg tooth to form two teeth., Conclusions: Our data agrees with previous hypotheses that during evolution one potential mechanism to generate a large tooth is through congrescence of multiple tooth germs and suggests that the ancestors of snakes could have had two egg teeth., (© 2019 Wiley Periodicals, Inc.)

During the formation of repetitive ectodermally derived organs such as mammary glands, lateral line and teeth, the tissue primordium iteratively initiates new structures. In the case of successional molar development, new teeth appear sequentially in the posterior region of the jaw from Sox2(+) cells in association with the posterior aspect of a pre-existing tooth. The sequence of molar development is well known, however, the epithelial topography involved in the formation of a new tooth is unclear. Here, we have examined the morphology of the molar dental epithelium and its development at different stages in the mouse in vivo and in molar explants. Using regional lineage tracing we show that within the posterior tail of the first molar the primordium for the second and third molar are organized in a row, with the tail remaining in connection with the surface, where a furrow is observed. The morphology and Sox2 expression of the tail retains characteristics reminiscent of the earlier stages of tooth development, such that position along the A-P axes of the tail correlates with different temporal stages. Sox9, a stem/progenitor cell marker in other organs, is expressed mainly in the suprabasal epithelium complementary with Sox2 expression. This Sox2 and Sox9 expressing molar tail contains actively proliferating cells with mitosis following an apico-basal direction. Snail2, a transcription factor implicated in cell migration, is expressed at high levels in the tip of the molar tail while E-cadherin and laminin are decreased. In conclusion, our studies propose a model in which the epithelium of the molar tail can grow by posterior movement of epithelial cells followed by infolding and stratification involving a population of Sox2(+)/Sox9(+) cells., (© 2015. Published by The Company of Biologists Ltd.)