伴DNA修复相关基因胚系突变的遗传易感性小儿白血病5例临床分析

目的探讨DNA修复相关基因胚系突变所致遗传易感性小儿白血病的诊断思路以及这类疾病临床、遗传学特征。方法收集并回顾性分析2017年5月—2020年1月确诊的5例DNA修复相关基因胚系突变的遗传易感性小儿白血病患儿的临床资料及遗传学、分子学资料。结果伴遗传易感性的白血病患儿中涉及DNA修复缺陷者5例,男2例,女3例。5例中1例TP53突变,2例PMS2突变,1例9p21.3p21.1缺失,1例CHEK2突变。结论白血病诊疗中应注意体貌异常及肿瘤家族史,不存在以上也不能除外肿瘤遗传易感性。需甄别结构性变异,重视基因突变及杂合性缺失两种形式,完全缓解后的拷贝数变异检测应更加积极。TP53c. 421T C p. C141R的胚系突变形式为致病性突变。PMS2的单等位基因突变也可导致典型的结构性错配修复综合征发生。DNA修复缺陷相关胚系突变本身不影响化疗反应,体细胞改变特征才是影响化疗疗效的关键因素。     

儿童遗传性肿瘤易感综合征和TP53基因种系突变

儿童遗传性肿瘤易感综合征是由于肿瘤相关基因的种系突变所导致的一类遗传性疾病,患者具有明显的肿瘤易感倾向。TP53基因的种系突变占到所有遗传性肿瘤的20%~30%,是最常见的肿瘤突变基因。通过对TP53基因的检测,可以帮助临床医师更好的对遗传性肿瘤患者及家庭成员进行管理。     

1例儿童先天性粒细胞减少症的基因诊断

目的应用基因诊断方法进一步提高对儿童先天性粒细胞减少症(CN)的认识和诊断水平。方法以1例儿童CN患者为研究对象,收集其临床资料、实验室检查结果,按序检测ELA2、GFI1、HAX1及WASp致病基因突变情况。依上述步骤对患儿分别进行疾病的临床及基因诊断并随访。结果参照诊断标准该患儿诊断为无遗传背景的散发性非综合征性CN;基因检测显示其携带已经报道的ELA2基因突变:c.164G>A;此外患儿中性粒细胞表面G-CSFR表达正常,G-CSFR胞内段未发现获得性截短性突变。结论基因突变检测证实1例儿童CN为ELA2基因突变所致,为该患儿未来的分组临床研究及基因治疗提供依据。     

以孤独症为主要表型的MYT1L基因突变嵌合体1例并文献复习北大核心CSCD

对2019年4月河南省儿童医院康复医学科就诊的1例孤独症谱系障碍(ASD)的MYT1L基因突变患儿临床表型和基因型进行回顾性分析。对患儿进行全基因组测序及拷贝数异常(CNVs)检测,并复习相关文献。该患儿存在MYT1L基因15号外显子错义突变(c.2186T>G,p.Met729Arg),患儿为嵌合体,突变率约为10%,该突变未在父母及患儿哥哥中出现。检索到MYT1L相关基因异常报道共18篇文献,共53例患者(含本例),包括22种点突变及30例携带包含MYT1L基因区域在内的2p25.3染色体条带微缺失患者。患者孤独症行为发生率为45.0%(18/40例)、超重/肥胖发生率为70.2%(33/47例)、智力障碍/全面发育迟缓发生率为96.2%(51/53例),嵌合体的症状相对较轻。提示MYT1L基因是ASD重要的易感基因,但嵌合体的症状较轻。ASD患儿共患肥胖或超重时应警惕可能存在MYT1L基因突变,可进行基因检测协助诊断并注意嵌合体存在的可能性,本研究扩大了ASD基因突变谱。     

丙酮酸脱氢酶复合物缺陷Leigh 综合征2 例临床及PDHA1基因分析

目的探讨PDHA1基因突变所致丙酮酸脱氢酶复合物E1α亚单位缺陷Leigh综合征的临床特点及诊断和治疗。方法回顾分析2例因发育落后就诊,磁共振扫描提示Leigh综合征,并经生化代谢及基因检测确诊患儿的临床资料。结果 2例男性患儿分别于1岁1个月、4个月就诊,发育落后,肌张力障碍,肌力低下;头颅磁共振检查发现双侧基底节区对称性损害;血清丙酮酸、乳酸明显增高,血氨基酸及酯酰肉碱谱无异常。基因分析发现2例患儿X染色体PDHA1基因分别存在c.615CG、c.605AG错义突变,均为未报道的新突变,证实为丙酮酸脱氢酶复合物E1α亚单位缺陷所致Leigh综合征。结论 PDHA1基因突变患儿临床表现复杂多样,对于不明原因的发育落后儿童,应注意线粒体病的可能,基因检测有助于诊断、治疗及遗传咨询。     

线粒体DNA缺失综合征1例临床及遗传学分析

目的分析由脱氧鸟苷激酶(DGUOK)基因突变导致的线粒体DNA缺失综合征(MDS)的临床特征、基因突变特点。方法回顾分析1例经二代测序确诊MDS患儿的临床资料。结果 36天男性婴儿,因低血糖、腹胀就诊,有肝功能异常、低血糖、乳酸增高。二代基因检测发现患儿DGUOK基因存在2个新发现突变,c.169dupT及c.630dupG,父母各携带1个突变,均为移码突变;产生截短蛋白。应用SWISS-MODE进行蛋白结构预测,对DGUOK结构造成影响,均未有文献报道。患儿住院治疗无好转,死亡。结论 DGUOK基因突变导致的MDS病情严重,预后极差。早期基因检测有助于诊断及遗传咨询。     

罕见ICF综合征1例临床表型和分子遗传学分析

目的探讨免疫缺陷、着丝粒不稳定和面部异常(ICF)综合征的临床特征和遗传特点。方法回顾分析1例ICF综合征患儿的临床资料和基因检测结果。结果男性患儿,4岁,有反复感染;面部特征为圆脸、眼距稍宽、下颌尖、鼻梁稍扁、内眦赘皮明显、耳位低。免疫学检测示IgA缺如。基因测序发现患儿DNMT3B基因存在一个纯合错义突变c. 2506 GA,父母为杂合携带者,确诊为ICF综合征I型。结论 DNMT3B基因突变可引发ICF综合征,基因检测有助于提高此类罕见病的诊断。     

WT1基因检测时机对Wilms肿瘤合并慢性肾脏疾病预后影响的回顾性队列研究

目的 分析在Wilms肿瘤合并慢性肾脏疾病(CKD)的患儿中WT1基因检测对诊断和长期预后的影响。方法 检索上海市肾脏发育与儿童肾脏病研究中心儿童肾脏病基因检测数据库,2001年1月1日至2018年12月31日明确WT1基因突变、年龄<18岁患儿,或Wilms肿瘤合并CKD 2~5期或肾病综合征或有蛋白尿的连续病例。按进展为终末期肾衰竭(ESRD)之前是否明确WT1基因突变分为早诊断组和晚诊断组,以ESRD为终点比较两组的预后。结果 22例患儿明确WT1基因的常染色体显性遗传突变,分别位于第8~9外显子/内含子。依据临床分型,10例为Denys-Drash综合征,3例为Fraiser综合征,9例表型为孤立型肾病综合征,5例合并假两性畸形。随访终点进入ESRD有15例,7例进入CKD 2~4期。应用生存曲线分析证实,早诊断组较晚诊断组进入ESRD病程显著延迟(P=0.011)。结论 在儿童Wilms肿瘤、肾病综合征/蛋白尿、慢性肾功能损害的患儿中,在肾功能进展恶化之前及早明确WT1基因突变,不仅有助于临床诊断分型,还能显著延缓进入ESRD病程。     

WT1基因检测时机对Wilms肿瘤合并慢性肾脏疾病预后影响的回顾性队列研究

目的 分析在Wilms肿瘤合并慢性肾脏疾病(CKD)的患儿中WT1基因检测对诊断和长期预后的影响。方法 检索上海市肾脏发育与儿童肾脏病研究中心儿童肾脏病基因检测数据库,2001年1月1日至2018年12月31日明确WT1基因突变、年龄<18岁患儿,或Wilms肿瘤合并CKD 2~5期或肾病综合征或有蛋白尿的连续病例。按进展为终末期肾衰竭(ESRD)之前是否明确WT1基因突变分为早诊断组和晚诊断组,以ESRD为终点比较两组的预后。结果 22例患儿明确WT1基因的常染色体显性遗传突变,分别位于第8~9外显子/内含子。依据临床分型,10例为Denys-Drash综合征,3例为Fraiser综合征,9例表型为孤立型肾病综合征,5例合并假两性畸形。随访终点进入ESRD有15例,7例进入CKD 2~4期。应用生存曲线分析证实,早诊断组较晚诊断组进入ESRD病程显著延迟(P=0.011)。结论 在儿童Wilms肿瘤、肾病综合征/蛋白尿、慢性肾功能损害的患儿中,在肾功能进展恶化之前及早明确WT1基因突变,不仅有助于临床诊断分型,还能显著延缓进入ESRD病程。     

儿童 Gitelman 综合征 3 例临床特点及基因分析

目的探讨儿童Gitelman综合征的临床及基因突变特点。方法回顾分析3例Gitelman综合征患儿的临床资料。结果 3例患儿均为男性,年龄分别为3、8、10岁。临床表现为低钾血症、低镁血症、碱中毒、高肾素血症、高醛固酮血症。基因检测显示存在SLC12A3基因的复合杂合突变,共发现SLC12A3基因的5个突变位点:c.179CT(Thr60Met)、c.248 GA(Arg 83 Gln)、c.2129 CA(Ser 710 X)、c.2660+1 GA、c.1456 GA(Asp 486 Asn)。患儿确诊后,经补钾、补镁、螺内酯治疗后病情好转。结论儿童出现低钾血症需注意Gitelman综合征,基因检测有助于明确诊断。     

Prenatal diagnosis in Li-Fraumeni syndrome

PURPOSE: The hallmark of Li-Fraumeni syndrome (LFS), a familial cancer syndrome, is constitutional TP53 mutation. The authors addressed the complex question of predictive prenatal genetic testing for cancer risk associated with inheritance of TP53 mutation. METHODS: A classic LFS family including the proband (a 20-month-old boy with rhabdomyosarcoma), his 36-year-old father with osteosarcoma, and his 40-year-old paternal aunt with bilateral breast cancer were identified as carriers of a TP53 germline mutation, a novel 1 base pair deletion in exon 5. A few years later, the mother became pregnant twice, and the parents requested prenatal diagnosis on each occasion. Genetic counseling, psychological evaluation, and support were provided by a multidisciplinary team including a pediatric oncologist, a geneticist, a psychosocial worker, a prenatal care provider, and an ethical representative. After providing overall information on LFS, including the high risk of developing secondary multiple neoplasms in LFS survivors, the committee approved prenatal diagnosis at the request of the family. RESULTS: In the two pregnancies, the two fetuses were found to be carriers of the same mutation. Nine years from diagnosis of the first tumor, the proband, and a month later his father, developed second tumors, multifocal osteosarcoma and leiomyosarcoma, respectively. CONCLUSIONS: Children with primary tumors belonging to LFS should be considered for screening for germline mutations and genetic counseling by a multidisciplinary team. Whether family members are found to be positive or negative as carriers, such measures may provide, by reducing uncertainty, psychological benefit to high-risk families.     

Malignant triton tumor in a patient with Li-Fraumeni syndrome and a novel TP53 mutation

We report a 3-year-old boy with a malignant triton tumor (MTT) involving the left masticator space with local invasion and regional lymph node metastasis. Family history and detection of a novel germline TP53 mutation confirmed his diagnosis of Li Fraumeni syndrome (LFS). MTT has not been previously described in association with LFS. This case along with a comprehensive review of the literature, illustrate the importance of both somatic and germline TP53 mutations in the pathogenesis MTT. The tumor could not be resected and he was successfully treated with intensive induction chemotherapy, irradiation, and high-dose chemotherapy with autologous stem cell transplantation.     

Germline p53 mutation in a Micronesian child with adrenocortical carcinoma and subsequent osteosarcoma

In 1990, an 18-month-old Micronesian girl was initially diagnosed with a right adrenocortical carcinoma. More than a decade later (2003), she was diagnosed with metastatic osteosarcoma with the primary in her right proximal fibula. Given this child's remarkable history of malignancy, she underwent testing for a genetic mutation that is associated with increased cancer formation. One such cancer syndrome is called Li-Fraumeni syndrome where approximately 70% of patients carry a genetic mutation in the p53 tumor suppressor gene. Patients with LFS are at risk for developing cancers of the breast, soft tissues, brain, bone, adrenal gland, and blood cells. Mutational analysis of our patient did reveal the presence of a germline mutation of the p53 tumor suppressor gene. She was found to have a base pair change (A-->C) at nucleotide 394 resulting in a lysine to glutamine amino acid change at codon 132 (K132Q), which remarkably has never been described in association with either adrenocortical carcinoma or osteosarcoma.     

How I approach hereditary cancer predisposition in a child with cancer

Approximately 10% of all children with cancer are affected by a monogenic cancer predisposition syndrome. This has important implications for both the child and her/his family. The assessment of hereditary cancer predisposition is a challenging task for clinicians and genetic counselors in daily routine. It includes consideration of tumor genetics, specific features of the patient, and the medical/family history. To keep up with the pace of this rapidly evolving and increasingly complex field of genetic susceptibility, we suggest a systematic approach for the evaluation of the child with cancer and her/his family by an interdisciplinary team specialized in hereditary cancer predisposition.     

Early detection of adrenocortical carcinoma in a child with Li–Fraumeni syndrome

We report an early detection of cancer in a child with Li–Fraumeni syndrome. The proband was a 3‐year‐old male with a primitive mesenchymal tumor. Genetic analysis showed a germline TP53 mutation in codon 220 exon 6, which changed TAT → TGT and resulted in a tyrosine‐to‐cysteine amino acid substitution (Tyr220Cys). The younger sister at risk was followed, and an asymptomatic adrenal cortical carcinoma was detected 3 years later. The report highlights the importance of genetic counseling and provides an example of early detection of cancers in childhood LFS carriers. Pediatr Blood Cancer 2009;52:541–544. © 2008 Wiley‐Liss, Inc.     

Composite adrenal anaplastic neuroblastoma and virilizing adrenocortical tumor with germline TP53 R248W mutation

Composite tumors are extremely rare. Such tumors in adrenal glands are usually of neuroendocrine-neural type and occur mostly in adults. Their pathogenesis remains elusive. We report a patient with composite neuroblastoma (NB), adrenocortical tumor (ACT), and Li-Fraumeni syndrome (LFS) with germline TP53 R248W mutation. LFS predisposes to the development of leukemia, sarcomas, adrenocortical and breast carcinomas, brain tumors and, questionably, NB. A unique correlation between a single TP53 mutation (R337H) and ACT has been reported in southern Brazilian children. It remains unclear at this time whether a similar association of NB and R248W in patients with LFS exists.     

A genome‐wide analysis of colorectal cancer in a child with Noonan syndrome

Noonan syndrome (NS) is a developmental syndrome caused by germline mutations in the Ras signaling pathway. No association has been shown between NS and pediatric colorectal cancer (CRC). We report the case of CRC in a pediatric patient with NS. The patient underwent whole genome sequencing. A germline SOS1 mutation c.1310T>C (p. Ile437Thr) confirmed NS diagnosis. No known hereditary cancer syndromes were identified. Tumor analysis revealed two mutations: a TP53 missense mutation c.481G>A (p. Ala161Tyr) and NCOR1 nonsense mutation c.6052C>T (p. Arg2018*). This report highlights the complexity of Ras signaling and the interplay between developmental syndromes and cancer.     

Radiation-sensitive genetically susceptible pediatric sub-populations

Major advances in pediatric cancer treatment have resulted in substantial improvements in survival. However, concern has emerged about the late effects of cancer therapy, especially radiation-related second cancers. Studies of childhood cancer patients with inherited cancer syndromes can provide insights into the interaction between radiation and genetic susceptibility to multiple cancers. Children with retinoblastoma (Rb), neurofibromatosis type 1 (NF1), Li-Fraumeni syndrome (LFS), and nevoid basal cell carcinoma syndrome (NBCCS) are at substantial risk of developing radiation-related second and third cancers. A radiation dose-response for bone and soft-tissue sarcomas has been observed in hereditary Rb patients, with many of these cancers occurring in the radiation field. Studies of NF1 patients irradiated for optic pathway gliomas have reported increased risks of developing another cancer associated with radiotherapy. High relative risks for second and third cancers were observed for a cohort of 200 LFS family members, especially children, possibly related to radiotherapy. Children with NBCCS are very sensitive to radiation and develop multiple basal cell cancers in irradiated areas. Clinicians following these patients should be aware of their increased genetic susceptibility to multiple primary malignancies enhanced by sensitivity to ionizing radiation.