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中国循证儿科杂志

中国循证儿科杂志 ›› 2024, Vol. 19 ›› Issue (1): 57-61.DOI: 10.3969/j.issn.1673-5501.2024.01.011

• 论著 • 上一篇    下一篇

PTEN基因致病性突变患儿51例病例系列报告

乔梦媛1a,吴冰冰1a,徐秀1b,李慧萍1b,王素娟1c,杨琳1d,周文浩1a, 2,王慧君1a   

  1.  1 国家儿童医学中心 复旦大学附属儿科医院上海，201102；a 分子医学中心，b 儿保科，c 康复科，d 内分泌遗传代谢科；2 广州医科大学附属妇女儿童医疗中心广州，510623
  • 收稿日期:2023-11-09 修回日期:2023-12-13 出版日期:2024-02-25 发布日期:2024-02-25
  • 通讯作者: 王慧君

51 children with pathogenic mutations in PTEN gene: A case series report

QIAO Mengyuan1a, WU Bingbing1a, XU Xiu1b, LI Huiping1b,  WANG Sujuan1c, YANG Lin1d, ZHOU Wenhao1a, 2, WANG Huijun1a   

  1. 1 Children's Hospital of Fudan University, National Children's Medical Center, Shanghai 201102, China; a Department of Neonatology, b Center for Molecular Medicine, c Department of Children Healthcare, d Department of Rehabilitation, e Department of Endocrinology; 2 Guangzhou Women and Children's Medical Center, Guangzhou 510623, China
  • Received:2023-11-09 Revised:2023-12-13 Online:2024-02-25 Published:2024-02-25
  • Contact: WANG Huijun

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摘要： 背景：PTEN基因突变可引起多种综合征表型，目前在成人中的表型谱研究较多，在儿童中相关研究较少。 目的：总结PTEN基因突变患儿的基因型和临床表型及二者的相关性。 设计：病例系列报告。 方法：纳入2016年1月1日至2023年1月31日复旦大学附属儿科医院分子医学中心经高通量测序发现有PTEN基因突变，且致病性评级为致病/可能致病的患儿，采集其临床特征和基因检测结果。 主要结局指标：临床表型与PTEN基因突变的关联。 结果：纳入51例确诊为PTEN基因致病性突变的患儿，男33例，基因检测时中位年龄为2岁（1天至13岁），中位随访年龄为5.2（3.6，6.5）岁，主诉以“发育落后”或“沟通障碍”为主（24例，47.0%）。共检出PTEN基因的41个致病/可疑致病突变，包括错义突变28个（68.3%），无义突变5个，移码突变4个，经典剪切位点突变3个，起始密码子突变1个；位于磷酸酶结构域28个（68.3%），位于C2结构域11个（24.4%），位于PIP2结合模体（PBD）和C-tail（C端尾）结构域各1个。c.388C>T(p.R130X)（5例）和c.302T>C(p.I101T)（3例）为热点突变位点。12个突变位点未见报道。22例患儿验证了突变来源，17例（77.3%）为新发突变。48例（94.1%）有巨头畸形。 42例（82.3%）诊断为神经发育障碍，其中语言发育迟缓36例（70%），大运动发育迟缓25例（49.0%），精细运动迟缓2例，平衡能力差3例，ASD 14例（27.4%），智力障碍13例（25.5%），注意力缺陷及多动障碍、学习困难各1例，3例（5.8%）有癫发作。11例（21.6%）发现肿瘤性疾病，发现时中位年龄为4.0（1.0~5.0）岁。8例（15.7%）有皮肤表现，包括阴茎雀斑、牛奶咖啡斑、黑痣、毛囊角化等。39例行头颅MR，35例（89.7%）发现异常，主要表现为脑血管周围间隙增宽（18例）、脑白质异常（6例）和脑室扩大（4例）。临床表型与PTEN基因的突变类型、突变位点的结构域分布均无明显关联。 结论：PTEN基因突变患儿以巨头畸形伴神经发育障碍（如发育迟缓、智力障碍和ASD）为主要表现，可有肿瘤发生、皮肤学表现、头颅MR异常等。

关键词: 巨头畸形, PTEN, 儿童, 肿瘤, 神经发育障碍

Abstract: Background：PTEN gene mutation can lead to a variety of syndrome phenotypes. At present, there are many studies on the phenotypic spectrum in adults, but few studies in children. Objective：To summarize the genotypes and clinical phenotypes of children with PTEN gene mutation and their correlation. Design：Case series report. Methods：Children with PTEN gene mutations, rated as being pathogenic or possibly pathogenic, discovered by high-throughput sequencing in the Molecular Medicine Center of the Children's Hospital of Fudan University from January 1, 2016 to January 31, 2023 were included. Their clinical data and gene testing results were intercepted. Main outcome measures：Clinical manifestations and PTEN gene mutations. Results：A total of 51 children with confirmed PTEN gene pathogenic mutations were included, including 33 males. The median age at the time of gene testing was 2 years (1d-13 years), and the median follow-up age was 5.2 years (3.6-6.5 years). The main complaints were developmental delay or communication disorder (24 cases in total, 47.0%). Forty-one pathogenic or suspected pathogenic variants were detected in the PTEN gene, including 28 missense mutations (68.3%), 5 nonsense mutations, 4 frameshift mutations, 3 classical splice site mutations, and 1 initiation codon mutation. Twenty-eight variants were located in the phosphatase domain (68.3%), 11 in the C2 domain (24.4%), and 1 in each of the PIP2 binding motif (PBD) and C-tail domains. c.388C>T(p.R130X) (5 cases) and c.302T>C(p.I101T) (3 cases) were hotspot mutation sites. Twelve mutation sites had not been previously reported. Mutation sources were verified in 22 children, of which 17 (77.3%) were de novo mutations. Macrocephaly was identified in 48 cases (94.1%). Forty-two cases (82.3%) were diagnosed with neurodevelopmental disorders, including language development delay in 36 cases (70%), large motor development delay in 25 cases (49.0%), fine motor development delay in 2 cases, poor balance in 3 cases, ASD in 14 cases (27.4%), intellectual disability in 13 cases (25.5%), attention deficit and hyperactivity disorder in 1 case, learning difficulty in 1 case, and epilepsy in 3 cases (5.8%). Tumor diseases were detected in 11 children (21.6%), with a median age of 4.0(1.0-5.0) years at the time of detection. Eight cases (15.7%) showed skin manifestations including penile freckles, café au lait spots, nevi, and hair follicle keratosis. Thirty-nine patients underwent cranial MRI, and 35 (89.7%) showed abnormalities, mainly including widened perivascular spaces (18 cases), white matter abnormalities (6 cases), and enlarged ventricles (4 cases). There was no significant difference in clinical phenotype, mutation type, and domain distribution of mutation sites. Conclusion：Children with PTEN gene mutations mainly present with macrocephaly with neurodevelopmental disorders such as developmental delay, intellectual disability, and autism spectrum disorder, and may have tumorigenesis, dermatological manifestations, and abnormal cranial MRI findings.

Key words: Macrocephaly, PTEN, Children, Tumor, Neurodevelopmental Disorders