The first two Chinese Myhre syndrome patients with the recurrent SMAD4 pathogenic variants: Functional consequences and clinical diversity.
复发性SMAD4 致病变异的前两个中国Myhre综合征患者: 功能后果和临床多样性。
- 作者列表："Li H","Cheng B","Hu X","Li C","Su J","Zhang S","Li L","Li M","Yang K","He S","Chen S","Wang H","Liu G","Shen Y
:Myhre syndrome is a rare autosomal dominant multi-organ disorder characterized by growth retardation, skeletal anomalies, muscular hypertrophy, joint stiffness, facial dysmorphism, deafness, cardiovascular disease, and abnormal sexual development. Here we described the first two Chinese Myhre syndrome patients diagnosed by whole-exome sequencing. They both had de novo c.1498A > G (p.Ile500Val) variant in SMAD4 and presented with key characteristics of Myhre syndrome but also revealed uncommon features (polydactyly in the girl and precocious puberty in the boy). We performed functional analysis on four previously reported SMAD4 pathogenic variants in Myhre syndrome patients using dual-luciferase assay. Our results revealed that the pathogenic variants resulted in a variable degree of increased transcription activity of target genes that contain the minimal SMAD binding elements in their promoter regions. The boy responded to the recombinant human growth hormone treatment with improved height but also led to hyperinsulinemia and advanced bone age. Because of his precocious puberty, we subsequently combined the recombinant human growth hormone and gonadotrophin-releasing hormone agonist treatments, which resulted in overall improved height. We reviewed the sexual features of reported Myhre syndrome cases and discussed the possible mechanism of SMAD4 variants in Myhre syndrome that lead to the abnormal hypothalamic-pituitary-gonadal axis.
: Myhre综合征是一种罕见的常染色体显性多器官疾病，以生长迟缓、骨骼异常、肌肉肥大、关节僵硬、面部畸形、耳聋、心血管疾病和性发育异常为特征。这里我们描述了前两个通过全外显子组测序诊断的中国Myhre综合征患者。他们都有de novo c.1498A > g (p。ile500Val) 在SMAD4 中变异，呈现Myhre综合征的关键特征，但也显示出不常见的特征 (女孩多指趾和男孩性早熟)。我们使用双荧光素酶试验对Myhre综合征患者中先前报道的 4 个SMAD4 致病变异进行了功能分析。我们的结果揭示了致病性变异导致了在其启动子区域中含有最小SMAD结合元件的靶基因转录活性的不同程度的增加。男孩对重组人生长激素治疗有反应，身高有所改善，但也导致高胰岛素血症和骨龄提前。由于他的性早熟，我们随后联合重组人生长激素和促性腺激素释放激素激动剂治疗，使身高总体改善。我们回顾了报道的Myhre综合征病例的性特征，并讨论了Myhre综合征中SMAD4 变异导致下丘脑-垂体-性腺轴异常的可能机制。
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.
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.
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.