Ⅰ型神经纤维瘤病合并CDK13相关疾病1例报道并文献复习

doi:10.3969/j.issn.1673-8640.2025.02.009

检验医学 ›› 2025, Vol. 40 ›› Issue (2): 154-159.DOI: 10.3969/j.issn.1673-8640.2025.02.009

• 精准医疗时代遗传性疾病基因检测专题 • 上一篇下一篇

Ⅰ型神经纤维瘤病合并CDK13相关疾病1例报道并文献复习

卢亚亚¹, 王亚琼¹, 彭慧芳², 娄丹¹()

1.河南科技大学第一附属医院，河南洛阳 471003
2.河南科技大学第一附属医院内分泌代谢中心河南省罕见病重点实验室河南洛阳 471003

收稿日期:2024-04-18 修回日期:2024-09-26 出版日期:2025-02-28 发布日期:2025-03-07
通讯作者: 娄丹，E-mail：loudan69@163.com。
作者简介:卢亚亚，女，1981年生，硕士，副主任医师，主要从事儿童生长发育相关研究。
基金资助:
河南省医学教育研究项目(Wjlx2022113);河南省医学科技攻关计划联合共建项目(LHGJ20210598)

Neurofibromatosis type 1 with CDK13-related disorder：a case report and literature

LU Yaya¹, WANG Yaqiong¹, PENG Huifang², LOU Dan¹()

1. The First Affiliated Hospital of Henan University of Science and Technology，Luoyang 471003，Henan，China
2. Endocrinology and Metabolism Center，the First Affiliated Hospital of Henan University of Science and Technology，Henan Key Laboratory of Rare Diseases，Luoyang 471003，Henan，China

Received:2024-04-18 Revised:2024-09-26 Online:2025-02-28 Published:2025-03-07

摘要/Abstract

摘要：

目的探讨Ⅰ型神经纤维瘤病（NF1）基因变异合并细胞周期蛋白依赖性激酶13（CDK13）基因变异患儿的临床特征和遗传学特点。方法收集1例NF1合并CDK13相关疾病患儿的临床资料，对患儿及其父母进行全外显子组测序，采用Sanger测序验证可疑变异，并进行家系分析。以“CDK13基因和NF1基因”或“CDK13 gene and NF1 gene”为检索词分别检索中国知网、万方数据知识服务平台和PubMed数据库建库至2024年2月的相关文献，总结同患NF1和CDK13相关疾病患者的临床表型和遗传学特征。结果患儿，男，13岁，主要临床表现为皮肤牛奶咖啡斑，矮小身材，特殊面容（上眼睑外斜、宽眼距、内眦赘皮、鼻梁宽），智力障碍。患儿存在NF1基因杂合变异c.3610C>G（p.Arg1204Gly）和CDK13基因移码突变c.484dupG（p.Ala162Glyfs*108）（杂合）。Sanger测序验证结果显示，患儿母亲携带NF1基因杂合变异，未携带CDK13基因移码突变；父亲均未携带。未检索到关于同患NF1和CDK13相关疾病的患者的文献。共检索到CDK13相关疾病文献11篇，文献复习结果显示，97例患者主要临床表现为智力障碍或发育迟缓、特殊面容、先天性心脏缺陷，致病变异以错义突变为主。结论 NF1基因变异可导致NF1。当发现有特殊面容的NF1患儿出现无法解释的现有表型或症状时，应注意2种遗传病同时存在的可能性。

关键词: Ⅰ型神经纤维瘤病基因, 细胞周期蛋白依赖性激酶13基因, 全外显子组测序, 智力发育障碍, 发育迟缓

Abstract:

Objective To investigate the clinical phenotypes and genetic characteristics of neurofibromatosis type 1（NF1） gene and cell cycle-dependent protein kinase 13（CDK13） gene. Methods The clinical data of a patient who was diagnosed with NF1 combined with CDK13-related disorder were collected retrospectively. Whole-exome sequencing was performed for the child and parents. The suspected variation was verified by Sanger sequencing and analyzed by connoisseur. Using "CDK13 gene and NF1 gene" as the keywords，relevant literatures were searched at CNKI，Wanfang Data and PubMed from the establishment of databases to February 2024. The clinical and genetic characteristics of this case of NF1 combined with CDK13-related disorder were summarized. Results The main clinical manifestations included café-au-lait macules，short stature，distinctive facial appearance（upslanting palpebral fissures，ocular hypertelorism，epicanthus and broad nasal bridge） and mental retardation. Whole-exome sequencing showed a heterogeneous variation CDK13 c.484dupG，p.Ala162Glyfs*108，NF1 c.3610C>G，p.Arg1204Gly. Sanger sequencing showed that the mother of the child carried a heterozygous mutation of NF1 gene，but did not carry a frameshit mutation of CDK13 gene. No literature with NF1 and CDK13-related disorder were found. A total of 11 papers were collected. The clinical manifestations of 97 patients were mental retardation or developmental delay，distinctive facial appearance and congenital heart defect. The main pathogenic variations were missense mutations. Conclusions NF1 gene mutation is the cause of NF1. Coexistence of double genetic diseases should be considered when NF1 patients with distinctive facial appearance and the existing phenotype or symptoms cannot be explained.

Key words: Neurofibromatosis type 1 gene, Cell cycle-dependent protein kinase 13 gene, Whole-exome sequencing, Mental retardation, Developmental delay

中图分类号:

R446.1

卢亚亚, 王亚琼, 彭慧芳, 娄丹. Ⅰ型神经纤维瘤病合并CDK13相关疾病1例报道并文献复习[J]. 检验医学, 2025, 40(2): 154-159.

LU Yaya, WANG Yaqiong, PENG Huifang, LOU Dan. Neurofibromatosis type 1 with CDK13-related disorder：a case report and literature[J]. Laboratory Medicine, 2025, 40(2): 154-159.

图/表 6

图1 本例患儿家系图注：正常男性； NF1女性患者； NF1伴CDK13相关疾病男性患者；先证者。

图2 本例患儿颅脑MRI 注：左枕叶、脑干、右侧小脑半球、双侧基底节区、双侧颞叶海马区多发异常信号。

图3 本例患儿腹部CT 注：左肾低密度灶，考虑囊肿。

图4 本例患儿及其父母NF1基因Sanger测序注：患儿NF1基因存在杂合变异c.3610C>G（p.Arg1204Gly），患儿母亲携带，父亲未携带。

图5 本例患儿及其父母CDK13基因Sanger测序注：患儿CDK13基因存在移码突变c.484dupG（p.Ala162Glyfs*108）（杂合），患儿父母亲均未携带。

表1 97例CDK13相关疾病患儿的临床特征

临床特征	已报道病例/[%（例/例）]	本例病例
智力障碍	80.9（76/94）	+
特殊面容	98.4（62/63）	+
异常脑结构	43.5（27/62）	+
心脏结构异常	42.4（39/92）	+
肾脏异常	42.4（14/33）	+

参考文献 21

[1]	KALLIONPÄÄ R A, UUSITALO E, LEPPÄVIRTA J, et al. Prevalence of neurofibromatosis type 1 in the Finnish population[J]. Genet Med, 2018, 20(9):1082-1086. DOI PMID
[2]	颜芳玲, 尹飞, 邓小鹿, 等. CDK13相关疾病1例病例报告[J]. 中国循证儿科杂志, 2021, 16(2):162-164. DOI
[3]	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.
[4]	SIFRIM A, HITZ M P, WILSDON A, et al. Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing[J]. Nat Genet, 2016, 48(9):1060-1065. DOI PMID
[5]	Deciphering Developmental Disorders Study. Prevalence and architecture of de novo mutations in developmental disorders[J]. Nature, 2017, 542(7642):433-438.
[6]	BOSTWICK B L, MCLEAN S, POSEY J E, et al. Phenotypic and molecular characterisation of CDK13-related congenital heart defects,dysmorphic facial features and intellectual developmental disorders[J]. Genome Med, 2017, 9(1):73.
[7]	UEHARA T, TAKENOUCHI T, KOSAKI R, et al. Redefining the phenotypic spectrum of de novo heterozygous CDK13 variants:three patients without cardiac defects[J]. Eur J Med Genet, 2018, 61(5):243-247.
[8]	HAMILTON M J, CASWELL R C, CANHAM N, et al. Heterozygous mutations affecting the protein kinase domain of CDK13 cause a syndromic form of developmental delay and intellectual disability[J]. J Med Genet, 2018, 55(1):28-38.
[9]	VAN DEN AKKER W M R, BRUMMELMAN I, MARTIS L M, et al. De novo variants in CDK13 associated with syndromic ID/DD:molecular and clinical delineation of 15 individuals and a further review[J]. Clin Genet, 2018, 93(5):1000-1007.
[10]	BOSTWICK B. CDK13-related disorder[EB/OL]. (2019-01-31)[2023-05-03]. https://www.ncbi.nlm.nih.gov/books/NBK536784/.
[11]	ROUXEL F, RELATOR R, KERKHOF J, et al. CDK13-related disorder:report of a series of 18 previously unpublished individuals and description of an epigenetic signature[J]. Genet Med, 2022, 24(5):1096-1107.
[12]	MORISON L D, VAN REYK O, FORBES E, et al. CDK13-related disorder:a deep characterization of speech and language abilities and addition of 33 novel cases[J]. Eur J Hum Genet, 2023, 31(7):793-804.
[13]	YAKUBOV R, AYMAN A, KREMER A K, et al. One-month-old girl presenting with pseudohypoaldosteronism leading to the diagnosis of CDK13-related disorder:a case report and review of the literature[J]. J Med Case Rep, 2019, 13(1):386.
[14]	KRKLJUS S, ABERNATHY C R, JOHNSON J S, et al. Analysis of CpG C-to-T mutations in neurofibromatosis type 1. Mutations in brief no. 129. Online[J]. Hum Mutat, 1998, 11(5):411. PMID
[15]	HEIM R A, KAM-MORGAN L N, BINNIE C G, et al. Distribution of 13 truncating mutations in the neurofibromatosis 1 gene[J]. Hum Mol Genet, 1995, 4(6):975-981. PMID
[16]	BERGOUG M, DOUDEAU M, GODIN F, et al. Neurofibromin structure,functions and regulation[J]. Cells, 2020, 9(11):2365.
[17]	NOVÁKOVÁ M, HAMPL M, VRÁBEL D, et al. Mouse model of congenital heart defects,dysmorphic facial features and intellectual developmental disorders as a result of non-functional CDK13[J]. Front Cell Dev Biol, 2019,7:155.
[18]	KEHRER-SAWATZKI H, COOPER D N. Challenges in the diagnosis of neurofibromatosis type 1(NF1) in young children facilitated by means of revised diagnostic criteria including genetic testing for pathogenic NF1 gene variants[J]. Hum Genet, 2022, 141(2):177-191.
[19]	HANNAH-SHMOUNI F, AL-SHAHOUMI R, BRADY L I, et al. Dual molecular diagnoses in a neurometabolic specialty clinic[J]. Am J Med Genet A, 2021, 185(3):766-773.
[20]	LIU L, SUN L, CHEN Y, et al. Delineation of dual molecular diagnosis in patients with skeletal deformity[J]. Orphanet J Rare Dis, 2022, 17(1):139. DOI PMID
[21]	谈丹丹, 刘艺丹, 范燕彬, 等. 同患两种罕见遗传病患儿9例的临床与遗传学特点[J]. 中华儿科杂志, 2023, 61(4):345-350.

Ⅰ型神经纤维瘤病合并CDK13相关疾病1例报道并文献复习

Neurofibromatosis type 1 with CDK13-related disorder：a case report and literature

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