新生儿Zhu-Tokita-Takenouchi-Kim综合征1例报告

刘伟娜; 皮亚雷; 白星宇; 陈惠芬

doi:10.7499/j.issn.1008-8830.2409076

PDF(733 KB)

HTML

中国当代儿科杂志 ›› 2025, Vol. 27 ›› Issue (3) : 373-376. DOI: 10.7499/j.issn.1008-8830.2409076

病例报告

新生儿Zhu-Tokita-Takenouchi-Kim综合征1例报告

刘伟娜¹, 皮亚雷², 白星宇¹, 陈惠芬¹

作者信息 +

Zhu-Tokita-Takenouchi-Kim syndrome in a neonate

LIU Wei-Na, PI Ya-Lei, BAI Xing-Yu, CHEN Hui-Fen

Author information +

文章历史 +

摘要

患儿，男，足月儿，生后16 min，因生后喉鸣、吸气性呼吸困难16 min入院，体格检查可见腭裂，胸骨左缘可闻及Ⅱ级收缩期吹风样杂音。全外显子组检测发现患儿SON基因存在c.5753-5756del（p.Val1918GlufsTer87）杂合变异，父母均未携带该变异，为新发变异，根据美国医学遗传学与基因组学学会指南，综合评级为“致病性变异”，该患儿最终诊断为Zhu-Tokita-Takenouchi-Kim（ZTTK）综合征。入院后给予对症支持治疗，随访至生后8个月，仍喉鸣明显，可少量吃奶，独坐不稳。该患儿是目前报道年龄最小者，其症状拓展了临床疾病谱，可为临床诊疗提供思路。

Abstract

The patient is a male neonate born at term. He was admitted 16 minutes after birth due to stridor and inspiratory respiratory distress. Physical examination revealed a cleft palate, and a grade II systolic ejection murmur was audible at the left sternal border. Whole exome sequencing identified a heterozygous variant in the SON gene, c.5753-5756del (p.Val1918GlufsTer87), which was absent in either parent, indicating a de novo mutation. According to the guidelines of the American College of Medical Genetics and Genomics, this was classified as a "pathogenic variant" leading to a diagnosis of Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome. Upon admission, symptomatic supportive treatment was provided. Follow-up at the age of 8 months revealed persistent stridor; the infant could only consume small amounts of milk and was unable to sit steadily. This patient represents the youngest reported case to date, and his symptoms expand the clinical spectrum of the disease, providing valuable insights for clinical diagnosis and treatment.

导出引用

刘伟娜, 皮亚雷, 白星宇, 陈惠芬. 新生儿Zhu-Tokita-Takenouchi-Kim综合征1例报告[J]. 中国当代儿科杂志. 2025, 27(3): 373-376 https://doi.org/10.7499/j.issn.1008-8830.2409076

LIU Wei-Na, PI Ya-Lei, BAI Xing-Yu, CHEN Hui-Fen. Zhu-Tokita-Takenouchi-Kim syndrome in a neonate[J]. Chinese Journal of Contemporary Pediatrics. 2025, 27(3): 373-376 https://doi.org/10.7499/j.issn.1008-8830.2409076

参考文献

1 Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5): 405-424. PMID: 25741868. PMCID: PMC4544753. DOI: 10.1038/gim.2015.30.
2 Slezak R, Smigiel R, Rydzanicz M, et al. Phenotypic expansion in Zhu-Tokita-Takenouchi-Kim syndrome caused by de novo variants in the SON gene[J]. Mol Genet Genomic Med, 2020, 8(10): e1432. PMID: 32705777. PMCID: PMC7549597. DOI: 10.1002/mgg3.1432.
3 Stark Z, Tan TY, Chong B, et al. A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders[J]. Genet Med, 2016, 18(11): 1090-1096. PMID: 26938784. DOI: 10.1038/gim.2016.1.
4 Kim JH, Shinde DN, Reijnders MRF, et al. De novo mutations in SON disrupt RNA splicing of genes essential for brain development and metabolism, causing an intellectual-disability syndrome[J]. Am J Hum Genet, 2016, 99(3): 711-719. PMID: 27545680. PMCID: PMC5011044. DOI: 10.1016/j.ajhg.2016.06.029.
5 Quintana Castanedo L, Sánchez Orta A, Maseda Pedrero R, et al. Skin and nails abnormalities in a patient with ZTTK syndrome and a de novo mutation in SON[J]. Pediatr Dermatol, 2020, 37(3): 517-519. PMID: 32045494. DOI: 10.1111/pde.14113.
6 Ahn EY, DeKelver RC, Lo MC, et al. SON controls cell-cycle progression by coordinated regulation of RNA splicing[J]. Mol Cell, 2011, 42(2): 185-198. PMID: 21504830. PMCID: PMC3137374. DOI: 10.1016/j.molcel.2011.03.014.
7 Zhu X, Petrovski S, Xie P, et al. Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios[J]. Genet Med, 2015, 17(10): 774-781. PMID: 25590979. PMCID: PMC4791490. DOI: 10.1038/gim.2014.191.
8 Tokita MJ, Braxton AA, Shao Y, et al. De novo truncating variants in SON cause intellectual disability, congenital malformations, and failure to thrive[J]. Am J Hum Genet, 2016, 99(3): 720-727. PMID: 27545676. PMCID: PMC5011061. DOI: 10.1016/j.ajhg.2016.06.035.
9 Takenouchi T, Miura K, Uehara T, et al. Establishing SON in 21q22.11 as a cause a new syndromic form of intellectual disability: possible contribution to Braddock-Carey syndrome phenotype[J]. Am J Med Genet A, 2016, 170(10): 2587-2590. PMID: 27256762. DOI: 10.1002/ajmg.a.37761.
10 辛红美, 赵建设, 律玉强, 等. 一例 SON基因杂合变异所致ZTTK综合征患儿的临床及遗传学分析 [J]. 中华医学遗传学杂志, 2022, 39(3): 316-320. PMID: 35315044. DOI: 10.3760/cma.j.cn511374-20210315-00225.
11 Pasca L, Politano D, Cavallini A, et al. A novel de novo heterozygous mutation in the SON gene associated with septo-optic dysplasia: a new phenotype[J]. Neuropediatrics, 2024, 55(3): 191-195. PMID: 37343586. DOI: 10.1055/a-2114-4387.
12 El-Said A, Morales JL, Rossi G, et al. Metabolic stroke as a clinical manifestation of Zhu-Tokita-Takenouchi-Kim syndrome: a case series[J]. Neurol Genet, 2023, 9(3): e200072. PMID: 37168776. PMCID: PMC10166595. DOI: 10.1212/NXG.0000000000200072.
13 Langford J, Vukadin L, Carey JC, et al. SON-related Zhu-Tokita-Takenouchi-Kim syndrome with recurrent hemiplegic migraine: putative role of PRRT2[J]. Neurol Genet, 2023, 9(3): e200062. PMID: 37057295. PMCID: PMC10091367. DOI: 10.1212/NXG.0000000000200062.
14 Tang S, You J, Liu L, et al. Expanding the mutational spectrum of ZTTK syndrome: a de novo variant with global developmental delay and malnutrition in a Chinese patient[J]. Mol Genet Genomic Med, 2023, 11(8): e2188. PMID: 37488749. PMCID: PMC10422072. DOI: 10.1002/mgg3.2188.
15 Yang L, Yang F. A de novo heterozygous variant in the SON gene is associated with Zhu-Tokita-Takenouchi-Kim syndrome[J]. Mol Genet Genomic Med, 2020, 8(11): e1496. PMID: 32926520. PMCID: PMC7667370. DOI: 10.1002/mgg3.1496.
16 Yang Y, Xu L, Yu Z, et al. Clinical and genetic analysis of ZTTK syndrome caused by SON heterozygous mutation c.394C>T[J]. Mol Genet Genomic Med, 2019, 7(11): e953. PMID: 31557424. PMCID: PMC6825855. DOI: 10.1002/mgg3.953.
17 Yi Z, Song Z, Li F, et al. A novel de novo frameshift variation in the SON gene causing severe global developmental delay and seizures in a Chinese female[J]. Int J Dev Neurosci, 2022, 82(3): 271-276. PMID: 35080253. DOI: 10.1002/jdn.10170.
18 Pietrobattista A, Della Volpe L, Francalanci P, et al. The expanding phenotype of ZTTK syndrome due to the heterozygous variant of SON gene focusing on liver involvement: patient report and literature review[J]. Genes (Basel), 2023, 14(3): 739. PMID: 36981010. PMCID: PMC10048019. DOI: 10.3390/genes14030739.
19 Vasquez-Forero DM, Masotto B, Ferrer-Avargues R, et al. Case report: a novel SON mutation in a Colombian patient with ZTTK syndrome[J]. Front Genet, 2023, 14: 1183362. PMID: 37476413. PMCID: PMC10354630. DOI: 10.3389/fgene.2023.1183362.
20 Pavone P, Saia F, Pappalardo X, et al. Novel malformations: Chiari type 1 and hydrocephalus in Zhu-Tokita-Takenouchi-Kim syndrome and novel SON variants[J]. Clin Case Rep, 2022, 10(12): e6529. PMID: 36540882. PMCID: PMC9755635. DOI: 10.1002/ccr3.6529.
21 Eid M, Bhatia S. Novel de novo heterozygous variants in the SON gene causing ZTTK syndrome: a case report of two patients and review of neurological findings[J]. Child Neurol Open, 2022, 9: 2329048X221119658. PMID: 36387043. PMCID: PMC9661544. DOI: 10.1177/2329048X221119658.
22 贠国俊, 王景刚, 李庆云, 等. SON基因变异致ZTTK综合征1例报告[J]. 临床儿科杂志, 2021, 39(11): 825-828. DOI: 10.3969/j.issn.1000-3606.2021.11.007.
23 赵培伟, 毕博, 张蕾, 等. SON基因异常致ZTTK综合征3例临床及遗传学分析[J]. 临床儿科杂志, 2023, 41(2): 113-116. DOI: 10.12372/jcp.2023.22e0180.
24 Na J, Cui L, Zhen Z, et al. Recurrent myocardial injury in a de novo SON mutation ZTTK syndrome patient: a case report[J]. BMC Pediatr, 2024, 24(1): 232. PMID: 38566089. PMCID: PMC10985872. DOI: 10.1186/s12887-024-04703-4.
25 Kushary ST, Revah-Politi A, Barua S, et al. ZTTK syndrome: clinical and molecular findings of 15 cases and a review of the literature[J]. Am J Med Genet A, 2021, 185(12): 3740-3753. PMID: 34331327. PMCID: PMC8595531. DOI: 10.1002/ajmg.a.62445.
26 Van Stechelman P, Wilson B, Grebe TA, et al. Hypogammaglobulinemia in 2 children with Zhu-Tokita-Takenouchi-Kim syndrome[J]. Ann Allergy Asthma Immunol, 2024, 133(1): 109-110. PMID: 38588913. DOI: 10.1016/j.anai.2024.04.005.
27 Halliday BJ, Baynam G, Ewans L, et al. Distinctive brain malformations in Zhu-Tokita-Takenouchi-Kim syndrome[J]. AJNR Am J Neuroradiol, 2022, 43(11): 1660-1666. PMID: 36229163. PMCID: PMC9731255. DOI: 10.3174/ajnr.A7663.
28 Dingemans AJM, Truijen KMG, Kim JH, et al. Establishing the phenotypic spectrum of ZTTK syndrome by analysis of 52 individuals with variants in SON[J]. Eur J Hum Genet, 2022, 30(3): 271-281. PMID: 34521999. PMCID: PMC8904542. DOI: 10.1038/s41431-021-00960-4.
29 Vukadin L, Park B, Mohamed M, et al. A mouse model of Zhu-Tokita-Takenouchi-Kim syndrome reveals indispensable SON functions in organ development and hematopoiesis[J]. JCI insight, 2024, 9(5): e175053. PMID: 38290089. PMCID: PMC10972584. DOI: 10.1172/jci.insight.175053.