Aberrant cell segregation in the craniofacial primordium and the emergence of facial dysmorphology in craniofrontonasal syndrome.


  • 影响因子:5.00
  • DOI:10.1371/journal.pgen.1008300
  • 作者列表:"Niethamer TK","Teng T","Franco M","Du YX","Percival CJ","Bush JO
  • 发表时间:2020-02-24

:Craniofrontonasal syndrome (CFNS) is a rare X-linked disorder characterized by craniofacial, skeletal, and neurological anomalies and is caused by mutations in EFNB1. Heterozygous females are more severely affected by CFNS than hemizygous males, a phenomenon called cellular interference that results from EPHRIN-B1 mosaicism. In Efnb1 heterozygous mice, mosaicism for EPHRIN-B1 results in cell sorting and more severe phenotypes than Efnb1 hemizygous males, but how craniofacial dysmorphology arises from cell segregation is unknown and CFNS etiology therefore remains poorly understood. Here, we couple geometric morphometric techniques with temporal and spatial interrogation of embryonic cell segregation in mouse mutant models to elucidate mechanisms underlying CFNS pathogenesis. By generating EPHRIN-B1 mosaicism at different developmental timepoints and in specific cell populations, we find that EPHRIN-B1 regulates cell segregation independently in early neural development and later in craniofacial development, correlating with the emergence of quantitative differences in face shape. Whereas specific craniofacial shape changes are qualitatively similar in Efnb1 heterozygous and hemizygous mutant embryos, heterozygous embryos are quantitatively more severely affected, indicating that Efnb1 mosaicism exacerbates loss of function phenotypes rather than having a neomorphic effect. Notably, neural tissue-specific disruption of Efnb1 does not appear to contribute to CFNS craniofacial dysmorphology, but its disruption within neural crest cell-derived mesenchyme results in phenotypes very similar to widespread loss. EPHRIN-B1 can bind and signal with EPHB1, EPHB2, and EPHB3 receptor tyrosine kinases, but the signaling partner(s) relevant to CFNS are unknown. Geometric morphometric analysis of an allelic series of Ephb1; Ephb2; Ephb3 mutant embryos indicates that EPHB2 and EPHB3 are key receptors mediating Efnb1 hemizygous-like phenotypes, but the complete loss of EPHB1-3 does not fully recapitulate the severity of CFNS-like Efnb1 heterozygosity. Finally, by generating Efnb1+/Δ; Ephb1; Ephb2; Ephb3 quadruple knockout mice, we determine how modulating cumulative receptor activity influences cell segregation in craniofacial development and find that while EPHB2 and EPHB3 play an important role in craniofacial cell segregation, EPHB1 is more important for cell segregation in the brain; surprisingly, complete loss of EPHB1-EPHB3 does not completely abrogate cell segregation. Together, these data advance our understanding of the etiology and signaling interactions underlying CFNS dysmorphology.


: 颅额鼻综合征 (CFNS) 是一种罕见的X连锁疾病,以颅面、骨骼和神经系统异常为特征,由efnb1 突变引起。杂合子女性比半合子男性受CFNS的影响更严重,这种现象被称为细胞干扰,由EPHRIN-B1 嵌合体引起。在Efnb1 杂合子小鼠中,EPHRIN-B1 的嵌合体导致细胞分选和比Efnb1 半合子雄性更严重的表型,但是细胞分离如何引起颅面畸形是未知的,因此CFNS的病因仍然知之甚少。在此,我们将几何形态测量技术与小鼠突变模型中胚胎细胞分离的时间和空间询问相结合,以阐明CFNS发病机制的潜在机制。通过在不同发育时间点和特定细胞群中产生EPHRIN-B1 嵌合体,我们发现EPHRIN-B1 在早期神经发育和后期颅面发育中独立调控细胞分离,与脸型出现数量差异相关。而Efnb1 杂合子和半合子突变胚胎的特定颅面形状变化在质量上相似,杂合子胚胎在数量上受到更严重的影响,表明Efnb1 嵌合体加剧了功能表型的丧失,而不是产生了新的效应。值得注意的是,Efnb1 的神经组织特异性破坏似乎并不导致CFNS颅面畸形,但其在神经嵴细胞来源的间充质内的破坏导致表型与广泛丢失非常相似。EPHRIN-B1 可以与EPHB1 、EPHB2 和EPHB3 受体酪氨酸激酶结合并发出信号,但与CFNS相关的信号伴侣尚不清楚。Ephb1; Ephb2; Ephb3 突变胚胎一个等位基因系列的几何形态计量学分析表明,EPHB2 和EPHB3 是介导Efnb1 半合子样表型的关键受体,但EPHB1-3 的完全缺失并不能完全概括CFNS样Efnb1 杂合性的严重程度。最后,通过生成Efnb1 +/Δ; Ephb1; Ephb2; Ephb3 四重敲除小鼠,我们确定了调节累积受体活性如何影响颅面发育中的细胞分离,发现EPHB2 和EPHB3 在颅面细胞分离中起重要作用,而EPHB1 在大脑中的细胞分离中更为重要; 令人惊讶的是,完全丧失EPHB1-EPHB3 并不能完全消除细胞分离。这些数据共同推进了我们对CFNS变形形态学基础的病因和信号相互作用的理解。



作者列表:["Peyroux E","Babinet MN","Cannarsa C","Madelaine C","Favre E","Demily C","Michael GA"]

METHODS::Impairments in social cognition have been frequently described in 22q11.2 deletion syndrome (22q11.2DS) and are thought to be a hallmark of difficulties in social interactions. The present study addresses aspects that are critical for everyday social cognitive functioning but have received little attention so far. Sixteen children with 22q11.2DS and 22 controls completed 1 task of facial expression recognition, 1 task of attribution of facial expressions to faceless characters involved in visually presented social interactions, and 1 task of attribution of facial expressions to characters involved in aurally presented dialogues. All three tasks have in common to involve processing of emotions. All participants also completed two tasks of attention and two tasks of visual spatial perception, and their parents completed some scales regarding behavioural problems of their children. Patients performed worse than controls in all three tasks of emotion processing, and even worse in the second and third tasks. However, they performed above chance level in all three tasks, and the results were independent of IQ, age and gender. The analysis of error patterns suggests that patients tend to coarsely categorize situations as either attractive or repulsive and also that they have difficulties in differentiating emotions that are associated with threats. An isolated association between the tasks of emotion and behaviour was found, showing that the more frequently patients with 22q11.2DS perceive happiness where there is not, the less they exhibit aggressive behaviour.

作者列表:["Sheridan GA","Nagle M","Howells C","Gallagher O","Kiely PJ","O'Toole P","Kelly PM","Moore DP"]

METHODS:BACKGROUND:We describe the first radiographic clinic in the literature for DDH and how this novel clinic can significantly improve the efficiency and cost-effectiveness of service in a tertiary referral centre. AIMS:A radiographic clinic for the management of developmental dysplasia of the hip was introduced in 2017 in our institution. We performed a detailed cost analysis to assess the economic savings made with the introduction of this new clinic. We assessed the efficiency of the service by identifying how many unnecessary outpatient visits were prevented. We also assessed the difference in times from referral to review between the two clinics. METHODS:Analysis of the clinic activity in 2017 was possible as all data was collected prospectively by the DDH CNS and stored in our database. Cost analysis was performed, and the savings made per patient along with the financial benefit to our institution was recorded. RESULTS:The new radiographic clinic reduced the cost of reviewing one patient by €162.51 per patient. There was a 73% discharge rate from the clinic which prevented 251 unnecessary patient visits to the outpatient department over the course of the year. There was a significant 11-day reduction in waiting times between referral and review when comparing the radiographic to the conventional clinic (p < 0.05). CONCLUSIONS:A radiographic clinic for the management of developmental dysplasia of the hip has a significant effect on the efficiency and overall cost-effectiveness of service provision in a tertiary referral centre.

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作者列表:["Grigoryan G","Korcek L","Eidelman M","Paley D","Nelson S"]

METHODS:INTRODUCTION:Triple pelvic osteotomy (TPO) involves periacetabular osteotomies of the ilium, ischium, and pubis to reorient the acetabulum. This operation is indicated in certain situations for the treatment of developmental dysplasia of the hip, dysplastic neuromuscular hips, and for containment of the femoral head in cases of Legg-Calvé-Perthes disease. METHODS:This retrospective cohort study compares radiographic outcomes of patients who underwent TPO using two different techniques and describes a novel single-incision direct lateral approach. TPO was performed on 22 patients by the senior author. The first 10 patients underwent TPO through a single-incision anterolateral approach. The last 12 patients underwent TPO using the direct lateral approach. Preoperative and postoperative pelvic radiographs were reviewed for each patient, and the migration index and center-edge angle were recorded. RESULTS:The migration index and center-edge angle were evaluated and were not found to be significantly different between the anterolateral and direct lateral groups. The direct lateral approach is described. CONCLUSION:The direct lateral approach for TPO is equivalent to the anterolateral approach on radiographic evaluation. Advantages of the direct lateral approach include direct visualization of the ischial osteotomy, effective mobilization of the acetabulum, and safety of the sciatic nerve.

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