【摘要】 背景 Phelan?McDermid综合征（PMS）由22q13.3缺失（通常包含SHANK3基因杂合缺失）或SHANK3基因致病变异引起，是一种罕见的发育障碍，具有突出的全面发育迟缓/智力低下、严重的语言发育落后、孤独症谱系障碍（ASD）等临床特征。关于PMS的临床表型研究大多依赖于患儿家长报告或问卷调查，具有广泛的异质性，很少有基于专业人员使用标准化测试工具对患儿进行直接现场评估再行基因型?神经发育表型的研究。目的 PMS的神经发育特征与22q13.3缺失大小的关联性研究。设计回顾性队列研究。方法 纳入2014年1月至2022年12月复旦大学附属儿科医院儿童保健科收治的确诊为PMS，并完成由专业人员评估的Griffiths精神发育量表?中文版（Griffiths）、孤独症诊断观察量表?第2版（ADOS?2）和VINELAND适应行为量表中文版（VINELAND）的患儿，且已经拷贝数变异验证22q13.3缺失片段的大小，多重连接依赖性探针扩增（MLPA）或Sanger验证确认SHANK3基因缺陷类型。根据缺失片段大小分为SHANK3基因致病变异（部分外显子缺失或者致病性点突变，Ⅰ组）和22q13.3缺失（包含整个SHANK3基因杂合缺失，Ⅱ组），行发育水平、孤独症严重程度和适应性差异性分析。按年龄分为≤6岁组和>6岁组，行发育水平差异性分析。主要结局指标基因型?神经发育特征表型关联。结果 39例患儿纳入本文分析，男20例，女19例，年龄为（52.7±21.9）月龄。Ⅰ组和Ⅱ组测试年龄、性别差异均无统计学意义。发育水平方面，Griffiths评估结果显示，Ⅰ组在运动、个人?社会、语言、手眼协调、表现能区的DQ平均值均高于Ⅱ组，但差异无统计学意义。按年龄分组，≤6岁组在大运动技能、手眼协调、表现能区的发育水平显著高于>6岁组。孤独症严重程度方面，ADOS?2量表严重程度评分在两组间差异无统计学意义。适应性能力方面，VINELAND评估结果显示，在四大领域和全量表的标准分中，Ⅰ组的平均标准分均高于Ⅱ组，但只有Ⅰ组的全量表标准分明显高于Ⅱ组，差异有统计学意义。进一步分析各次领域的DQ值，Ⅰ组平均DQ值均高于Ⅱ组，但只有在表达性次领域、个人次领域、日常生活技巧领域、粗大动作次领域、动作技巧和全量表中，两组间的DQ值差异有统计学意义。结论 仅SHANK3基因缺陷足以产生PMS的神经特征表型，其两个领域（日常生活技巧、动作技巧）、三个次领域（表达性、个人、粗大动作）及全量表的适应性水平显著高于22q13.3缺失患儿，而运动、个人?社会、语言、手眼协调、表现能区的发育水平及孤独症症状的严重程度和22q13.3缺失患儿差异无统计学意义。学龄前期患儿较学龄期患儿具有更高的发育水平，因此建议早期评估，早期干预，定期进行综合评估，及时作出相应的调整和干预。更多还原

【Abstract】 Background Phelan?McDermid syndro me(PMS) is caused by deletion of 22q13.3(typically including heterozy?gous deletion of the SHANK3 gene) or pathogenic variants in the SHANK3 gene. It is a rare developmental disorder characterized by prominent global developmental delay/intellectual disability, severe language developmental delay, and autism spectrum disor?der(ASD) features. Most studies on the clinical phenotype of PMS relied on parental reports or questionnaires, which had exten?sive heterogeneity, and there were few studies that directly evaluate patients through standardized assessment tools by professionals to study the genotype?neurodevelopmental phenotype. Objective To investigate the association between neurodevelopmental fea?tures and the size of the 22q13.3 deletion in PMS. Design Retrospective cohort study. Methods Patients were admitted to the de?partment of pediatric health at Children’s Hospital of Fudan University from January 2014 to December 2022. Patients diagnosed with PMS and confirmed through CNV verification of the size of the 22q13.3 deletion fragment, MLPA or Sanger verification of the SHANK3 gene defect types, and who completed assessments using the Griffiths Mental Developmental Scales ? Chinese version(Griffiths), Autism Diagnostic Observation Schedule?2nd Edition(ADOS?2), and VINELAND adaptive behavior scales?chinese version, were included in this study. Patients were further divided into two groups based on the size of the deletion fragments: Group I, consisting of patients with pathogenic variants in the SHANK3 gene(partial exons deletion or pathogenic point muta?tions), and Group II, consisting of patients with a 22q13.3 deletion that includes a heterozygous deletion of the entire SHANK3 gene. The developmental level, severity of autism, and adaptive abilities were analyzed. Age group was divided into ≤6 years old group and >6 years old group for the analysis of developmental differences. Main outcome measures The correlation between genotype and neurodevelop mental features. Results A total of 39 patients were included in the analysis(20 males and 19 fe?males), with an average age of 52.7±21.9 months. There were no statistically significant differences between Group I and Group II regarding testing age and gender. In terms of developmental level, Griffiths showed that Group I had higher average developmental quotient(DQ) scores than Group II in the areas of gross motor, personal?social, language, hand?eye coordination and perfor?mance, but the differences were not statistically significant. When divided by age group, the ≤6 years old group had significantly higher developmental levels in gross motor skills, hand?eye coordination, and performance compared to the >6 years old group. Re?garding autism severity, there was no significant difference between the two groups based on ADOS?2 severity scores. In terms of adaptive abilities, VINELAND showed that Group I had higher average standard scores than Group II in all four domains and the overall scale, but only the overall scale standard score of Group I was significantly higher than that of Group II, with a statistically significant difference. Further analysis of DQ values in each subdomain showed that Group I had higher average DQ scores than Group II. However, statistically significant differences were only found in the expressive subdomain, personal subdomain, daily liv?ing skills domain, gross motor subdomain, motor skills and overall scale. Conclusion SHANK3 gene defects alone are sufficient to produce the neurobehavioral phenotypes of PMS. Patients with SHANK3 gene defects have significantly higher adaptive levels in two major domains(daily living skills and motor skills) and three subdomains(expressive language, personal, gross motor) as well as the overall scale compared to patients with 22q13.3 deletions alone. However, there were no significant differences in develop?mental levels or autism symptom severity between patients with SHANK3 gene defects and those with 22q13.3 deletions alone. Pre?school patients exhibited higher developmental levels than school?age patients, suggesting the importance of early evaluation, early intervention, regular comprehensive assessments to monitor children’s developmental progress.更多还原